Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I) as defined herein, or a pharmaceutically acceptable salt, or an in-vivo-hydrolysable ester thereof, are useful as antibacterial agents. Processes for their manufacture and pharmaceutical compositions containing them are described.

This application is the 371 of PCT/GB 99/01753, filed on Jun. 6, 1999.

The present invention relates to antibiotic compounds and in particularto antibiotic compounds containing a substituted oxazolidinone ring.This invention further relates to processes for their preparation, tointermediates useful in their preparation, to their use as therapeuticagents and to pharmaceutical compositions containing them.

The international microbiological community continues to express seriousconcern that the evolution of antibiotic resistance could result instrains against which currently available antibacterial agents will beineffective. In general, bacterial pathogens may be classified as eitherGram-positive or Gram-negative pathogens. Antibiotic compounds witheffective activity against both Gram-positive and Gram-negativepathogens are generally regarded as having a broad spectrum of activity.The compounds of the present invention are regarded primarily aseffective against Gram-positive pathogens because of their particularlygood activity against such pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci,Streptococci and mycobacteria, are particularly important because of thedevelopment of resistant strains which are both difficult to treat anddifficult to eradicate from the hospital environment once established.Examples of such strains are methicillin resistant staphylococcus(MRSA), methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant Streptococcus pneumoniae and multiply resistantEnterococcus faecium.

The major clinically effective antibiotic for treatment of suchresistant Gram-positive pathogens is vancomycin. Vancomycin is aglycopeptide and is associated with nephrotoxicity and ototoxicity.Furthermore, and most importantly, antibacterial resistance tovancomycin and other glycopeptides is also appearing. This resistance isincreasing at a steady rate rendering these agents less and lesseffective in the treatment of Gram-positive pathogens.

Certain antibacterial compounds containing an oxazolidinone ring havebeen described in the art (for example, Walter A. Gregory et al inJ.Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem.1992, 35, 1156-1165). Such antibacterial oxazolidinone compounds with a5-methylacetamide sidechain may be subject to mammalian peptidasemetabolism. Furthermore, bacterial resistance to known antibacterialagents may develop, for example, by (i) the evolution of active bindingsites in the bacteria rendering a previously active pharmacophore lesseffective or redundant, and/or (ii) the evolution of means to chemicallydeactivate a given pharmacophore. Therefore, there remains an ongoingneed to find new antibacterial agents with a favourable pharmacologicalprofile, in particular for compounds containing new pharmacophores.

We have discovered a class of antibiotic compounds containing a newclass of substituted oxazolidinone ring which has useful activityagainst Gram-positive pathogens including MRSA and MRCNS and, inparticular, against various strains exhibiting resistance to vancomycinand against E. faecium strains resistant to both aminoglycosides andclinically used β-lactams.

Accordingly the present invention provides a compound of the formula(I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysableester thereof,

wherein X is —O—, —S—, —SO— or —SO₂—;

HET is a C-linked 5-membered heteroaryl ring containing 2 to 4heteroatoms independently selected from N, O and S, which ring isoptionally substituted on an available carbon atom by 1 or 2substituents independently selected from (1-4C)alkyl, amino,(1-4C)alkylamino, (1-4C)alkoxy and halogen, and/or on an availablenitrogen atom (provided that the ring is not thereby quaternised) by(1-4C)alkyl;

Q is selected from Q1 to Q9:

wherein R² and R³ are independently hydrogen or fluoro;

wherein A₁ is carbon or nitrogen; B₁ is O or S (or, in Q9 only, NH);X_(q) is O, S or N—R¹ (wherein R¹ is hydrogen, (1-4C)alkyl orhydroxy-(1-4C)alkyl); and wherein in Q7 each A₁ is independentlyselected from carbon or nitrogen, with a maximum of 2 nitrogenheteroatoms in the 6-membered ring, and Q7 is linked to T via any of theA₁ atoms (when A₁ is carbon), and linked in the 5-membered ring via thespecified carbon atom, or via A₁ when A₁ is carbon; Q8 is linked to Tvia either of the specified carbon atoms in the 5-membered ring, andlinked in the benzo-ring via either of the two specified carbon atoms oneither side of the linking bond shown; and Q9 is linked via either ofthe two specified carbon atoms on either side of the linking bond shown;

wherein T is selected from the groups in (TA) to (TD) below (whereinAR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 aredefined hereinbelow);

(TA) T is selected from the following groups:

(TAa) AR1, AR1-(1-4C)alkyl-, AR2(carbon linked), AR3;

(TAb) AR1-CH(OH), AR2-CH(OH)—, AR3-CH(OH)—;

(TAc) AR1-CO—, AR2-CO—, AR3-CO—, AR4-CO—;

(TAd) AR1-O—, AR2-CO—, AR3-O—;

(TAe) AR1-S(O)_(q)—, AR²-S(O)_(q)—, AR3-S(O)_(q)— (q is 0.1 or 2);

(TAf) an optionally substituted N-linked (fully unsaturated) 5-memberedheteroaryl ring system containing 1, 2 or 3 nitrogen atoms;

(TAg) a carbon linked tropol-3-one or tropol-4-one, optionallysubstituted in a position not adjacent to the linking position; or

(TB) T is selected from the following groups:

(TBa) halo or (1-4C)alkyl

{optionally substituted by one or more groups each independentlyselected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl, cyano, halo,trifluoromethyl, (1-4C)alkoxycarbonyl, —NRvRw, (1-6C)alkanoylamino,(1-4C)alkoxycarbonylamino, N—(1-4C)alkyl-N—(1-6C)alkanoylamino,(1-4C)alkylS(O)_(q)— (q is 0, 1 or 2), CY1, CY2 or AR1};

(TBb) —NRv¹Rw¹;

(TBc) ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl,2-cyano-2-(1-4C)alkyl)ethenyl, 2-nitroethenyl,2-nitro-2-(1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl,2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl;

(TBd) R¹⁰CO—, R¹⁰S(O)_(q)— (q is 0, 1 or 2) or R¹⁰CS—

wherein R¹⁰ is selected from the following groups:

(TBda) CY1 or CY2;

(TBdb) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw, ethenyl,2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl,2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl,2-(1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl,2-(AR1)ethenyl or 2-(AR2)ethenyl; or

(TBdc) (1-4C)alkyl {optionally substituted as defined in (TBa) above, orby (1-4C)alkylS(O)_(p)NH— or (1-4C)alkylS(O)_(p)—((1-4C)alkyl)N— (p is 1or 2)};

wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl;Rv¹ is hydrogen, (1-4C)alkyl or (3-8C)cycloalkyl; Rw¹ is hydrogen,(1-4C)alkyl, (3-8C)cycloalkyl, (1-4C)alkyl-CO— or (1-4C)alkylS(O)_(q)—(q is 1 or 2); or

(TC) T is selected from the following groups:

(TCa) an optionally substituted, fully saturated 4-membered monocyclicring containing 1 heteroatom selected from O, N and S (optionallyoxidised), and linked via a ring nitrogen or sp³ carbon atom;

(TCb) an optionally substituted 5-membered monocyclic ring containing 1heteroatom selected from O, N and S (optionally oxidised), and linkedvia a ring nitrogen atom or a ring sp³ or sp² carbon atom, whichmonocyclic ring is fully saturated other than (where appropriate) at alinking sp² carbon atom;

(TCc) an optionally substituted 6- or 7-membered monocyclic ringcontaining 1 or 2 heteroatoms independently selected from O, N and S(optionally oxidised), and linked via a ring nitrogen atom or a ring sp³or sp² carbon atom, which monocyclic ring is fully saturated other than(where appropriate) at a linking sp² carbon atom; or

(TD) T is selected from the following groups:

(TDa) a bicyclic spiro-ring system containing 0, 1 or 2 ring nitrogenatoms as the only ring heteroatoms, the structure consisting of a 5- or6-membered ring system (linked via a ring nitrogen atom or a ring sp³ orsp2 carbon atom) substituted (but not adjacent to the linking position)by a 3-, 4- or 5-membered spiro-carbon-linked ring; which bicyclic ringsystem is

(i) fully saturated other than (where appropriate) at a linking sp²carbon atom;

(ii) contains one —N(Rc)— group in the ring system (at least two carbonatoms away from the linking position when the link is via a nitrogenatom or an sp² carbon atom) or one —N(Rc)— group in an optionalsubstituent (not adjacent to the linking position) and is

(iii) optionally further substituted on an available ring carbon atom;or

(TDb) a 7-, 8- or 9-membered bicyclic ring system (linked via a ringnitrogen atom or a ring sp³ or sp² carbon atom) containing 0, 1 or 2ring nitrogen atoms (and optionally a further O or S ring heteroatom),the structure containing a bridge of 1, 2 or 3 carbon atoms; whichbicyclic ring system is

(i) fully saturated other than (where appropriate) at a linking sp²carbon atom;

(ii) contains one O or S heteroatom, or one —N(Rc)— group in the ring(at least two carbon atoms away from the linking position when the linkis via a nitrogen atom or an s carbon atom) or one —N(Rc)— group in anoptional substituent (not adjacent to the linking position) and is

(iii) optionally further substituted on an available ring carbon atom;

wherein Rc is selected from groups (Rc1) to (Rc5):

(Rc1) (1-6C)alkyl {optionally substituted by one or more (1-4C)alkanoylgroups (including geminal disubstitution) and/or optionallymonosubstituted by cyano, (1-4C)alkoxy, trifluoromethyl,(1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR definedhereinafter), (1-4C)alkylS(O)_(q)— (q is 0, 1 or 2); or, on any but thefirst carbon atom of the (1-6C)alkyl chain, optionally substituted byone or more groups (including geminal disubstitution) each independentlyselected from hydroxy and fluoro, and/or optionally monosubstituted byoxo, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N—(1-4C)alkyl-N—(1-6C)alkanoylamino, (1-4C)alkylS(O)_(p)NH— or(1-4C)alkylS(O)_(p)—((1-4C)alkyl)N— (p is 1 or 2)};

(Rc2) R¹³CO—, R¹³SO₂— or R¹³CS—

wherein R¹³ is selected from (Rc2a) to (Rc2e):

(Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;

(Rc2b) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw [whereinRv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], ethenyl,2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl,2-nitroethenyl, 2-nitro-2-(1-4C)alkyl)ethenyl,2-((1-4C)alkylaminocarbonyl)ethenyl, 2-(1-4C)alkoxycarbonyl)ethenyl,2-(AR1)ethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl;

(Rc2c) (1-10C)alkyl {optionally substituted by one or more groups(including geminal disubstitution) each independently selected fromhydroxy, (1-10C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, phosphoryl[—O—P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives thereof],phosphiryl [—O—P(OH)₂ and mono- and di-(1-4C)alkoxy derivativesthereof], and amino; and/or optionally substituted by one group selectedfrom phosphonate [phosphono, —P(O)(OH)₂, and mono- and di-(1-4C)alkoxyderivatives thereof], phosphinate [—P(OH)₂ and mono- and di-(1-4C)alkoxyderivatives thereof], cyano, halo, trifluoromethyl,(1-4C)alkoxycarbonyl, 1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino,di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N—(1-4C)alkyl-N—(1-6C)alkanoylamino, (1-4C)alkylaminocarbonyl,di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O)_(p)—((1-4C)alkyl)N—,fluoro(1-4C)alkylS(O)_(p)NH—, fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—,(1-4C)alkylS(O)_(q)—, CY1, CY2, AR1, AR2, AR3, AR1-O—, AR2-O—, AR3-O—,AR1-S(O)_(q)—, AR2-S(O)_(q)—, AR3-S(O)_(q)—, AR1-NH—, AR2-NH—, AR3-NH—(p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3bversions of AR2 and AR3 containing groups};

(Rc2d) R¹⁴C(O)O(1-6C)alkyl wherein R¹⁴ is AR1, AR2, (1-4C)alkylamino,benzyloxy-(1-4C)alkyl or (1-10C)alkyl {optionally substituted as definedfor (Rc2c)};

(Rc2e) R¹⁵O— wherein R¹⁵ is benzyl, (1-6C)alkyl {optionally substitutedas defined for (Rc2c)}, CY1, CY2 or AR2b;

(Rc3) hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl,2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl,2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-(AR1)ethenyl,2-(AR2)ethenyl, or of the formula (Rc3a)

wherein X⁰⁰ is —OR¹⁷, —SR¹⁷, —NHR¹⁷and —N(R¹⁷)₂;

wherein R¹⁷ is hydrogen (when X⁰⁰ is —NHR¹⁷ and —N(R¹⁷)₂), and R¹⁷ is(1-4C)alkyl, phenyl or AR2 (when X⁰⁰ is —OR¹⁷, —SR¹⁷ and —NHR¹⁷); andR¹⁶ is cyano, nitro, (1-4C)alkylsulfonyl, (4-7C)cycloalkylsulfonyl,phenylsulfonyl, (1-4C)alkanoyl and (1-4C)alkoxycarbonyl;

(Rc4) trityl, AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b;

(Rc5) RdOC(Re)═CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)— orRiNHC(Rj)═CHC(═O)— wherein Rd is (1-6C)alkyl; Re is hydrogen or(1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf ishydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl,—NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl], (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy,di-(1-4C)alkylamino(2-6C)alkoxy; Rg is (1-6C)alkyl, hydroxy or(1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl; Ri is hydrogen,(1-6C)alkyl, AR1, AR2, AR2a, AR2b and Rj is hydrogen or (1-6C)alkyl;

wherein

AR1 is an optionally substituted phenyl or optionally substitutednaphthyl;

AR2 is an optionally substituted 5- or 6-membered, fully unsaturated(i.e with the maximum degree of unsaturation) monocyclic heteroaryl ringcontaining up to four heteroatoms independently selected from O, N and S(but not containing any O—O, O—S or S—S bonds), and linked via a ringcarbon atom, or a ring nitrogen atom if the ring is not therebyquaternised;

AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systemsretaining some, but not the full, degree of unsaturation), linked via aring carbon atom or linked via a ring nitrogen atom if the ring is notthereby quaternised;

AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having nounsaturation), linked via a ring carbon atom or linked via a ringnitrogen atom;

AR3 is an optionally substituted 8-, 9- or 10-membered, fullyunsaturated (i.e with the maximum degree of unsaturation) bicyclicheteroaryl ring containing up to four heteroatoms independently selectedfrom O, N and S (but not containing any O—O, O—S or S—S bonds), andlinked via a ring carbon atom in either of the rings comprising thebicyclic system;

AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systemsretaining some, but not the full, degree of unsaturation), linked via aring carbon atom, or linked via a ring nitrogen atom if the ring is notthereby quaternised, in either of the rings comprising the bicyclicsystem;

AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having nounsaturation), linked via a ring carbon atom, or linked via a ringnitrogen atom, in either of the rings comprising the bicyclic system;

AR4 is an optionally substituted 13- or 14-membered, fully unsaturated(i.e with the maximum degree of unsaturation) tricyclic heteroaryl ringcontaining up to four heteroatoms independently selected from O, N and S(but not containing any O—O, O—S or S—S bonds), and linked via a ringcarbon atom in any of the rings comprising the tricyclic system;

AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systemsretaining some, but not the full, degree of unsaturation), linked via aring carbon atom, or linked via a ring nitrogen atom if the ring is notthereby quaternised, in any of the rings comprising the tricyclicsystem;

CY1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexylring;

CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring.

In this specification, where it is stated that a ring may be linked viaan sp² carbon atom, which ring is fully saturated other than (whereappropriate) at a linking sp² carbon atom, it is to be understood thatthe ring is linked via a C═C double bond.

In another embodiment, (Rc1) is as defined above other than the optionalphenyl substituent on (1-6C)alkyl is optionally substituted as for AR1defined hereinafter; and (Rc2c), is as defined above and furtherincludes carboxy as an optional substituent on R¹³ as (1-10C)alkyl.

(TAf) When T is an optionally substituted N-linked (fully unsaturated)5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms,it is preferably selected from a group of formula (TAf1) to (TAf6) below(particularly (TAf1), (TA2), (TAf4) and (TAf5), and especially (TAf1)and/or (TAf2)). The above preferred values of (TAf) are particularlypreferred when present in Q1 or Q2, especially Q1, and when X is —O—.

wherein:

R⁶ is selected (independently where appropriate) from hydrogen,(1-4C)alkyl, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, carbamoyl and cyano;

R⁴ and R⁵ are independently selected from hydrogen, halo,trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)_(q)— (q is0, 1 or 2), (1-4C)alkanoyl, (1-4C)alkoxycarbonyl,(2-4C)alkanoyloxy-(1-4C)alkyl, benzoxy-(1-4C)alkyl, (2-4C)alkanoylamino,—CONRvRw, —NRvRw and (1-4C)alkyl {optionally substituted by hydroxy,trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)_(q)— (q is0, 1 or 2), (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, —CONRvRw, —NRvRw;wherein RvRw is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl};

or R⁴ is selected from one of the groups in (TAfa) to (TAfc) below, or(where appropriate) one of R⁴ and R⁵ is selected from the above list ofR⁴ and R⁵ values, and the other is selected from one of the groups in(TAfa) to (TAfc) below:

(TAfa) a group of the formula (TAfa1)

wherein Z⁰ is hydrogen or (1-4C)alkyl;

X⁰ and Y⁰ are independently selected from hydrogen, (1-4C)alkyl,(1-4C)alkoxycarbonyl, halo, cyano, nitro, (1-4C)alkylS(O)_(q)— (q is 0,1 or 2), RvRwNSO₂—, trifluoromethyl, pentafluoroethyl, (1-4C)alkanoyland —CONRvRw [wherein Rv is hydrogen or (1-4C)alkyl;

Rw is hydrogen or (1-4C)alkyl); or

one of X⁰ and Y⁰ is selected from the above list of X⁰ and Y⁰ values,and the other is selected from phenyl, phenylcarbonyl, —S(O)_(q)-phenyl(q is 0, 1 or 2), N-(phenyl)carbamoyl, phenylaminosulfonyl, AR2,(AR2)-CO—, (AR2)-S(O)_(q)— (q is 0, 1 or 2), N-(AR2)carbamoyl and(AR2)aminosulfonyl; wherein any phenyl group in (TAfa) may be optionallysubstituted by up to three substituents independently selected from(1-4C)alkyl, cyano, trifluoromethyl, nitro, halo and(1-4C)alkylsulfonyl;

(TAfb) an acetylene of the formula —≡—H or —≡—(1-4C)alkyl;

(TAfc) —X¹—Y¹—AR2, —X¹—Y¹—AR2a, —X¹—Y¹—AR2b, —X¹—Y¹—AR3, —X¹—Y¹—AR3a or—X¹—Y¹—AR3b;

wherein X¹ is a direct bond or —CH(OH)— and

Y¹ is —(CH₂)_(m)—, —(CH₂)_(n)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—,—CONH—(CH₂)_(m)—, —C(═S)NH—(CH₂)_(m)— or —C(═O)O—(CH₂)_(m)—;

or wherein X¹ is —(CH₂)_(n)— or —CH(Me)—(CH₂)_(m)— and

Y¹ is —(CH₂)_(m)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)—,—C(═S)NH—(CH₂)_(m)—, —C(═O)O—(CH₂)_(m)— or —S(O)_(q)—(CH₂)_(m—;)

or wherein X¹ is —CH₂O—, —CH₂NH— or —CH₂N((1-4C)alkyl)— and

Y¹ is —CO—(CH₂)_(m), —CONH—(CH₂)_(m)— or —C(═S)NH—(CH₂)_(m)—; andadditionally Y¹ is —SO₂— when X¹ is —CH₂NH— or —CH₂N((1-4C)alkyl)—, andY¹ is —(CH₂)_(m)— when X¹ is —CH₂O— or —CH₂N((1-4C)alkyl)—; wherein n is1, 2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and when Y¹ is—(CH₂)_(m)—NH—(CH₂)_(m)— each m is independently selected from 0, 1, 2or 3.

It is to be understood that when a value for —X¹— is a two-atom link andis written, for example, as —CH₂NH— it is the left hand part (—CH₂—here) which is bonded to the group of formula (TAf1) to (TAf6) and theright hand part (—NH— here) which is bonded to —Y¹— in the definition in(TAfc). Similarly, when —Y¹— is a two-atom link and is written, forexample, as —CONH— it is the left hand part of —Y¹—(—CO— here) which isbonded to the right hand part of —X¹—, and the right hand part of—Y¹—(—NH— here) which is bonded to the AR2, AR2a, AR2b, AR3, AR3a orAR3b moiety in the definition in (TAfc).

Preferably R⁶ is hydrogen or (1-4C)alkyl, and R⁴ and R⁵ areindependently selected from hydrogen, (1-4C)alkyl or one of R⁴ and R⁵ isselected from group (TAfa). Other preferable substituents on the (TAf1)to (TAf6) are illustrated in the accompanying Examples.

(TAg) When T is a carbon linked tropol-3-one or tropol-4-one, optionallysubstituted in a position not adjacent to the linking position (TAg), itis preferably selected from a group of formula (TAg1), (TAg2) or (TAg3).The above preferred values of (TAg) are particularly preferred whenpresent in Q1 or Q2, especially Q1, and when X is —O—.

wherein R⁷ is selected from

(TAga)hydrogen, (1-4C)alkyl {optionally substituted by one or twosubstituents (excluding geminal disubstitution) independently selectedfrom fluoro, hydroxy, (1-4C)alkoxy and —NRvRw]}; or

(TAgb)R⁸—O—, R⁸—S—, R⁸—NH— or R⁸R⁸—N—;

wherein R⁸ is selected (independently where appropriate) from hydrogen,(1-4C)alkyl or (3-8C)cycloalkyl {both optionally substituted by one ortwo substituents (excluding geminal disubstitution) independentlyselected from hydroxy, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and —NRvRw},(2-4C)alkenyl {optionally substituted by one or two —NRvRwsubstituents}, (1-4C)alkanoyl {optionally substituted by one or twosubstituents independently selected from —NRvRw and hydroxy},phenyl-(1-4C)alkyl or pyridyl-(1-4C)alkyl {the phenyl and pyridyl(preferably pyridin-4-yl) rings being optionally substituted by one ortwo —NRvRw substituents}; or

(TAgc)morpholino, thiomorpholino, pyrrolidino {optionally independentlysubstituted in the 3- and/or 4-positions by (1-4C)alkyl}, piperidinosubstituted in the 4-position by R⁹—, R⁹—O—, R⁹—S—, R⁹—NH— or R⁹R⁹—N—;wherein R⁹ is selected (independently where appropriate) from hydrogen,(1-4C)alkyl {optionally substituted by one or two (excluding geminaldisubstitution) hydroxy, (1-4C)alkoxy, (1-4C)alkoxycarbonyl or —NRvRw}and piperazino {optionally substituted in the 4-position by (1-4C)alkyl,(3-8C)cycloalkyl, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl or(1-4C)alkylsulfonyl, and optionally independently substituted in the 3-and/or 5-positions by (1-4C)alkyl}; wherein Rv is hydrogen or(1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl.

(TC) Preferred values for the optional substituents and groups definedin (TCa) to (TCc) are defined by formulae (TC1) to (TC4):

wherein in (TC1): >A₃—B₃— is >C(Rq)—CH(Rr)— and G is —O—, —S—, —SO—,—SO₂— or >N(Rc);

wherein in (TC2): m1 is 0, 1 or 2; >A₃—B₃— is >C═C(Rr)—or >C(Rq)—CH(Rr)— and G is —O—, —S—, —SO—, —SO₂— or >N(Rc);

wherein in (TC3) m1 is 0, 1 or 2; >A₃—B₃— is >C(Rq)—CH(Rr)— (other thanwhen Rq and Rr are both together hydrogen) and G is —O—, —S—, —SO—,—SO₂— or >N(Rc);

wherein in (TC4): n1 is 1 or 2; o1 is 1 or 2 and n1+o1=2 or 3; >A₃—B₃—is >C═C(Rr)— or >C(Rq)—CH(Rr)— or >N—CH₂— and G is —O—, —S—, —SO—, —SO₂—or >N(Rc); Rp is hydrogen, (1-4C)alkyl (other than when suchsubstitution is defined by >A₃—B₃—), hydroxy, (1-4C)alkoxy or(1-4C)alkanoyloxy;

wherein in (TC1), (TC2) and (TC4); m1, n1 and o1 are as definedhereinbefore: >A₃—B₃— is >N—CH₂— and G is>C(R¹¹)(R¹²), >C═O, >C—OH, >C—(1-4C)alkoxy, >C═N—OH, >C═N—(1-4C)alkoxy, >C═N—NH—(1-4C)alkyl,>C═N—N(1-4C)alkyl)₂ (the last two (1-4C)alkyl groups above in G beingoptionally substituted by hydroxy) or >C═N—N—CO—(1-4C)alkoxy; wherein >represents two single bonds;

Rq is hydrogen, hydroxy, halo, (1-4C)alkyl or (1-4C)alkanoyloxy;

Rr is (independently where appropriate) hydrogen or (1-4C)alkyl;

R¹¹ is hydrogen, (1-4C)alkyl, fluoro(1-4C)alkyl,(1-4C)alkyl-thio-(1-4C)alkyl or hydroxy-(1-4C)alkyl and R¹² is—[C(Rr)(Rr)]_(m2)—N(Rr)(Rc) wherein m2 is 0, 1 or 2;

and, other than the ring substitution defined by G, >A₃—B₃— and Rp, eachring system may be optionally further substituted on a carbon atom notadjacent to the link at >A₃— by up to two substituents independentlyselected from (1-4C)alkyl, fluoro(1-4C)alkyl (includingtrifluoromethyl), (1-4C)alkyl-thio-(1-4C)alkyl, hydroxy-(1-4C)alkyl,amino, amino-(1-4C)alkyl, (1-4C)alkanoylamino,(1-4C)alkanoylamino-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl,AR-oxymethyl, AR-thiomethyl, oxo (═O) (other than when G is >N—Rc and Rcis group (Rc2) defined hereinbefore) or independently selected from Rc;and also hydroxy or halo (the last two optional substituents only when Gis —O— or —S—);

wherein AR is as defined for formula (IP) hereinafter; Rc is selectedfrom groups (Rc1) to (Rc5) defined hereinbefore.

For the avoidance of doubt, ( )_(m1), ( )_(n1) and ( )_(o1) indicate(—CH₂—)_(m1), (—CH₂—)_(n1) and (—CH₂—)_(o1) respectively (optionallysubstituted as described above).

In the above definition of (TC1) to (TC4) and of the further optionalsubstituents, AR is preferably AR2, and the further optionalsubstituents are preferably not selected from the values listed for Rc.A preferred value for G is >N(Rc) or >C(R¹¹)(R¹²).

Particularly preferred values for the optional substituents and groupsdefined in (TCa) to (TCc), and (TC1) to (TC4) are contained in thefollowing definitions (TC5) to (TC11):

wherein Rc has any of the values listed hereinbefore or hereinafter.

Especially preferred are (TC5), (TC6), (TC7) and (TC9), most especially(TC5) in which Rc has any of the values listed hereinbefore orhereinafter (especially R¹³CO— with the preferable R¹³ values givenhereinafter). In (TC5) Rc is preferably selected from the group (Rc2),especially R¹³CO— with the preferable R¹³ values given hereinafter. In(TC7) Rc is preferably selected from group (Rc3) or (Rc4).

The above preferred values of (TCa) to (TCc) are particularly preferredwhen present in Q1 or Q2, especially Q1, and when X is —O— (especiallywhen HET is isoxazole).

(TDa) When T is a bicyclic spiro-ring system as defined in (TDa), it ispreferably selected from a group of formula (TDa1) to (TDa9). The abovepreferred values of(TDa) are particularly preferred when present in Q1or Q2, especially Q1, and when X is —O—.

wherein;

(i) the A₄ linking group is a nitrogen atom or an sp³ or sp² carbon atom(with the double bond, where appropriate, orientated in eitherdirection); and

(ii) one of the ring carbon atoms at positions marked * and ** isreplaced by one of the following groups:—NRc—, >CH—NHRc, >CH—NRc—(1-4C)alkyl, >CH—CH₂—NHRc,>CH—CH₂—NRc—(1-4C)alkyl [wherein a central —CH₂— chain link isoptionally mono- or di-substituted by (1-4C)alkyl]; with the provisosthat positions marked * are not replaced by —NH— in the ring containingthe A₄ link when A₄ is a nitrogen atom or an sp² carbon atom, and thatpositions marked * are not replaced by —NH— in the three membered ringin (TDa1), (TDa4) and (TDa5); and

(iii) the ring system is optionally (further) substituted on anavailable ring carbon atom by up to two substituents independentlyselected from (1-4C)alkyl, fluoro(1-4C)alkyl (includingtrifluoromethyl), (1-4C)alkyl-thio-(1-4C)alkyl, hydroxy-(1-4C)alkyl,amino, amino-(1-4C)alkyl, (1-4C)alkanoylamino,(1-4C)alkanoylamino-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl,AR2-oxymethyl, AR2-thiomethyl, oxo (═O) (other than when the ringcontains an >N—Rc and Rc is group (Rc2)) and also hydroxy or halo;

wherein Rc has any of the values listed hereinbefore or hereinafter.

(TDb) When T is a 7-, 8- or 9-membered bicyclic ring system containing abridge of 1, 2 or 3 carbon atoms as defined in (TDb), it is preferablyselected from a group defined by the ring skeletons shown in formulae(TDb1) to (TDb14):

wherein;

(i) the ring system contains 0, 1 or 2 ring nitrogen atoms (andoptionally a further O or S ring heteroatom), and when present the ringnitrogen, O or S heteroatom/s are at any position other than as part ofthe 3-membered ring in (TDb1);

(ii) the ring system is linked via a ring nitrogen atom or a ring sp³ orsp² carbon atom (with the double bond, where appropriate, orientated ineither direction) from any position in either ring [other than from abridgehead position or from an sp² carbon atom in the 4-membered ring in(TDb2), (TDb6) and (TDb11)];

(iii) one of the ring carbon atoms at a position not adjacent to thelinking position, is replaced (other than when the ring contains an O orS heteroatom) by one of the following groups —NRc— [not at a bridgeheadposition], >C(H)—NHRc, >C(H)—NRc—(1-4C)alkyl, >C(H)—CH₂—NHRc,>C(H)—CH₂—NRc—(1-4C)alkyl [wherein the hydrogen atom shown in bracketsis not present when the replacement is made at a bridgehead position andwherein a central —CH₂— chain link is optionally mono- or di-substitutedby (1-4C)alkyl]; with the proviso that when the ring system is linkedvia a ring nitrogen atom or an sp² carbon atom any replacement of a ringcarbon atom by —NRc—, O or S is at least two carbon atoms away from thelinking position; and

(iv) the ring system is optionally (further) substituted on an availablering carbon atom as for the bicyclic spiro-ring systems described in(TDa); wherein Rc has any of the values listed hereinbefore orhereinafter.

It will be appreciated that unstable anti-Bredt compounds are notcontemplated in this definition (i.e. compounds wraith structures(TDb3), (TDb4), (TDb7), (TDb8), (TDb9), (TDb12), (TDb13) and (TDb14) inwhich an sp² carbon atom is directed towards a bridgehead position).

Particularly preferred values of (TDb) are the following structures offormula (TDb4), (TDb8) and/or (TDb9); wherein Rc has any of the valueslisted hereinbefore or hereinafter. The above preferred values of (TDb)are particularly preferred when present in Q1 or Q2, especially Q1, andwhen X is —O—.

In another embodiment there is provided a compound of the formula (I)which is defined by the formula (IP) below, or apharmaceutically-acceptable salt or an in-vivo hydrolysable esterthereof, wherein

X is —O—, —S—, —SO— or —SO₂—;

HET is a C-linked 5-membered heteroaryl ring containing 2 or 3heteroatoms independently selected from N, O and S (with the provisothat there are no O—O, O—S or S—S bonds), which ring is optionallysubstituted on any available C atom (provided that when a N atom isadjacent to the X-link, there is no substitution on any C atom that isadjacent to this N atom) by 1 or 2 substituents independently selectedfrom (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy and halogen,and/or on an available N atom (provided that the ring is not therebyquaternised), by (1-4C)alkyl;

wherein: R² and R³ are independently hydrogen or fluoro;

Rp is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;

>A—B— is of the formula >C═C(Rr)—, >CHCHRr—, >C(OH)CHRr— or >N—CH₂—(>represents two single bonds) wherein Rr is hydrogen or (1-4C)alkyl;

D is —O—, —S—, —SO—, —SO₂— or >NRcp;

Rp1 and Rp2 are independently oxo (═O) [but not when Rcp is group (PC)below], (1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl,hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl,AR-thiomethyl (wherein AR is as defined hereinbelow) or independently asdefined for Rcp hereinbelow with the proviso that Rp1 and Rp2 are notphenyl, benzyl, AR (as defined hereinbelow), a tetrazole ring system,cyclopentyl or cyclohexyl; and when D is —O— or —S—, Rp1 and Rp2 areadditionally independently hydroxy or bromo;

wherein Rcp is selected from (PA) to (PE) below:

(PA) hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl,2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl;

(PB) phenyl, benzyl, AR (as defined hereinbelow) or a tetrazole ringsystem [optionally mono-substituted in the 1- or 2-position of thetetrazole ring by (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl or(1-4C)alkanoyl] wherein the tetrazole ring system is joined to thenitrogen in >NRcp by a ring carbon atom;

(PC) R^(13p)CO—, R^(13p)SO₂— or R^(13p)CS— wherein R^(13p) is selectedfrom (PCa) to (PCf):

(PCa) AR (as defined hereinbelow);

(PCb) cyclopentyl or cyclohexyl, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl or1,4-dioxan-2-yl [optionally mono- or di-substituted by substituentsindependently selected from (1-4C)alkyl (including geminaldisubstitution), hydroxy (but excluding 1,3-dioxolan-4-yl,1,3-dioxan-4-yl or 1,4-dioxan-2-yl substituted by hydroxy),(1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano andtrifluoromethyl];

(PCc) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, amino,(1-4C)alkylamino, di((1-4C)alkyl)amino, 2-(5- or 6-memberedheteroaryl)ethenyl, 2-(5- or 6-membered (partially) hydrogenatedheteroaryl)ethenyl, 2-phenylethenyl [wherein the heteroaryl or phenylsubstituent is optionally substituted on an available carbon atom by upto three substituents independently selected from (1-4C)alkoxy, halo,cyano and (for the phenyl substituent only) (1-4C)alkylsulfonyl];

(PCd) (1-10C)alkyl [optionally substituted by one or more groups(including geminal disubstitution) each independently selected fromhydroxy and amino, or optionally monosubstituted by cyano, halo,(1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl,(1-4C)alkoxycarbonyl, (1-4C)alkylamino, di((1-4C)alkyl)amino,(1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N—(1-4C)alkyl-N—(2-6C)alkanoylamino, (1-4C)alkylS(O)_(p)NH—,(1-4C)alkylS(O)_(p)—((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)_(p)NH—,fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, phosphono,(1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl,(1-4C)alkylS(O)_(q)—, phenyl, naphthyl, phenoxy, naphthoxy, phenylamino,naphthylamino, phenylS(O)_(q)—, naphthylS(O)_(q)— [wherein said phenyland naphthyl groups are optionally substituted by up to threesubstituents independently selected from (1-4C)alkoxy, halo and cyano],or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0, 1 or 2];

(PCe) R^(14p)C(O)O(1-6C)alkyl wherein R^(14p) is an optionallysubstituted 5- or 6-membered heteroaryl, optionally substituted phenyl,(1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted(1-10C)alkyl;

(PCf) R^(15p)O— wherein R^(15p) is benzyl or optionally substituted(1-6C)alkyl;

(PD) RdOC(Re)═CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)— orRiNHC(Rj)═CHC(═O)— wherein Rd is (1-6C)alkyl; Re is hydrogen or(1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf ishydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl,amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy,(1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy,(1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy; Rg is(1-6C)alkyl, hydroxy or (1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl; Riis hydrogen, (1-6C)alkyl, optionally substituted phenyl or an optionallysubstituted 5- or 6-membered heteroaryl [and (partially) hydrogenatedversions thereof] and Rj is hydrogen or (1-6C)alkyl;

(PE) R^(16p)CH(R^(17p))(CH₂)_(mp)— wherein mp is 0 or 1; R^(17p) isfluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonylor hydroxy, (provided that when mp is 0, R^(17p) is not fluoro orhydroxy) and R^(16p) is hydrogen or (1-4C)alkyl;

wherein AR is optionally substituted phenyl, optionally substitutedphenyl(1-4C)alkyl, optionally substituted naphthyl, optionallysubstituted 5- or 6-membered heteroaryl;

wherein AR is also an optionally substituted 5/6 or 6/6 bicyclicheteroaryl ring system, in which the bicyclic heteroaryl ring systemsmay be linked via an atom in either of the rings comprising the bicyclicsystem, and wherein both the mono- and bicyclic heteroaryl ring systemsare linked via a ring carbon atom and may be (partially) hydrogenated;

wherein CY is selected from:

(i) cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenylring;

(ii) 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryloxy, 5- or6-membered heteroaryl-S(O)_(q)—, 5- or 6-membered heteroarylamino [and(partially) hydrogenated versions thereof] and

(iii) 5/6 or 6/6 bicyclic heteroaryl, 5/6 or 6/6 bicyclic heteroaryloxy,5/6 or 6/6 bicyclic heteroaryl-S(O)_(q)—, 5/6 or 6/6 bicyclicheteroarylamino [and (partially) hydrogenated versions thereof]; whereinq is 0, 1 or 2 and any of the afore-mentioned ring systems in CY may beoptionally substituted by up to three substituents independentlyselected from halo, (1-4C)alkyl [including geminal disubstitution whenCY is a cycloalkyl or cycloalkenyl ring in (i)], acyl, oxo andnitro-(1-4C)alkyl.

For the avoidance of doubt, phosphono is —P(O)(OH)₂;(1-4C)alkoxy(hydroxy)-phosphoryl is a mono-(1-4C)alkoxy derivative of—O—P(O)(OH)₂; and di-(1-4C)alkoxyphosphoryl is a di-(1-4C)alkoxyderivative of —O—P(O)(OH)₂.

In this embodiment of formula (IP) a ‘5- or 6-membered heteroaryl’ and‘heteroaryl (monocyclic) ring’ means a 5- or 6-membered aryl ringwherein (unless stated otherwise) 1, 2 or 3 of the ring atoms areselected from nitrogen, oxygen and sulfur. Unless stated otherwise, suchrings are fully aromatic. Particular examples of 5- or 6-memberedheteroaryl ring systems are furan, pyrrole, pyrazole, imidazole,triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole,isothiazole, thiazole and thiophene.

Particular examples of 5-membered heteroaryl rings containing 2 or 3heteroatoms independently selected from N, O and S (with the provisothat there are no O—O, O—S or S—S bonds; and in an alternativeembodiment, also no N—S bonds) are pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole; and also in analternative embodiment, isothiazole, 1,2,5-thiadiazole,1,2,4-thiadiazole or 1,2,3-thiadiazole.

In this embodiment of formula (IP) a ‘5/6 or 6/6 bicyclic heteroarylring system’ and ‘heteroaryl (bicyclic) ring’ means an aromatic bicyclicring system comprising a 6-membered ring fused to either a 5 memberedring or another 6 membered ring, the bicyclic ring system containing 1to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Unlessstated otherwise, such rings are fully aromatic. Particular examples of5/6 and 6/6 bicyclic ring systems are indole, benzofuran, benzimidazole,benzothiophene, benzisothiazole, benzoxazole, benzisoxazole,pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline,phthalazine, cinnoline and naphthyridine.

Particular optional substituents for alkyl, phenyl (and phenylcontaining moieties) and naphthyl groups and ring carbon atoms inheteroaryl (mono or bicyclic) rings in R^(14p), R^(15p), Ri and ARinclude halo, (1-4C)alkyl, hydroxy, nitro, carbamoyl,(1-4C)alkylcarbamoyl, di-((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl,trifluoromethoxy, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino,(1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkanoyl, (1-4C)alkoxy,(1-4C)alkylS(O)₂amino, (1-4C)alkanoylamino, benzoylamino, benzoyl,phenyl (optionally substituted by up to three substituents selected fromhalo, (1-4C)alkoxy or cyano), furan, pyrrole, pyrazole, imidazole,triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole,isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl,(1-4C)alkoxyimino(1-4C)alkyl, hydroxy-(1-4C)alkyl, halo-(1-4C)alkyl,nitro(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl,(1-4C)alkanesulfonamido, aminosulfonyl, (1-4C)alkylaminosulfonyl anddi-((1-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups andheteroaryl (mono- or bicyclic) rings in R^(14p), Ri and AR may be mono-or di-substituted on ring carbon atoms with substituents independentlyselected from the above list of particular optional substituents.

In this specification the term ‘alkyl’ includes straight chained andbranched structures. For example, (1-6C)alkyl includes propyl, isopropyland tert-butyl. However, references to individual alkyl groups such as“propyl” are specific for the straight chained version only, andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. A similar conventionapplies to other radicals, for example halo(1-4C)alkyl includes1-bromoethyl and 2-bromoethyl.

There follow particular and suitable values for certain substituents andgroups referred to in this specification. These values may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore, or hereinafter.

Examples of (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, andpropyl and isopropyl; examples of (1-6C)alkyl include methyl, ethyl,propyl, isopropyl, pentyl and hexyl; examples of (1-10C)alkyl includemethyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl andnonyl; examples of (1-4C)alkanoylamino-1-4C)alkyl includeformamidomethyl, acetamidomethyl and acetamidoethyl; examples ofhydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of(1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and2-cyano-2-ethylethenyl; examples of 2-nitro-2-(1-4C)alkyl)ethenylinclude 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of2-((1-4C)alkylaminocarbonyl)ethenyl include2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl;examples of (2-4C)alkenyl include allyl and vinyl; examples of(2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoylinclude formyl, acetyl and propionyl; examples of (1-4C)alkoxy includemethoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxyinclude methoxy, ethoxy, propoxy and pentoxy; examples of(1-4C)alkylthio include methylthio and ethylthio; examples of(1-4C)alkylamino include methylamino, ethylamino and propylamino;examples of di-((1-4C)alkyl)amino include dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino anddipropylamino; examples of halo groups include fluoro, chloro and bromo;examples of (1-4C)alkylsulfonyl include methylsulfonyl andethylsulfonyl; examples of (1-4C)alkoxy-1-4C)alkoxy and(1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy,2-ethoxyethoxy and 3-methoxypropoxy; examples of(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy,2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkylS(O)₂amino includemethylsulfonylamino and ethylsulfonylamino; examplesof(1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido,acetamido and propionylamino; examples of (1-4C)alkoxycarbonylaminoinclude methoxycarbonylamino and ethoxycarbonylamino; examples ofN—(1-4C)alkyl-N—(1-6C)alkanoylamino include N-methylacetamido,N-ethylacetamido and N-methylpropionamido; examples of(1-4C)alkylS(O)_(p)NH— wherein p is 1 or 2 include methylsulfinylamino,methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examplesof (1-4C)alkylS(O)_(p)((1-4C)alkyl)N— wherein p is 1 or 2 includemethylsulfinylmethylamino, methylsulfonylmethylamino,2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples offluoro(1-4C)alkylS(O)_(p)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examplesof fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylmethylamino andtrifluoromethylsulfonylmethlylamino examples of(1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl andethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl includedi-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl;examples of (1-4C)alkylS(O)_(q)— wherein q is 0, 1 or 2 includemethylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl andethylsulfonyl; examples of phenylS(O)_(q) and naphthylS(O)_(q)— whereinq is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl andnaphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively;examples of benzyloxy-(1-4C)alkyl include benzyloxymethyl andbenzyloxyethyl; examples of a (3-4C)alkylene chain are trimethylene ortetramethylene; examples of (1-6C)alkoxy-(1-6C)alkyl includemethoxymethyl, ethoxymethyl and 2-methoxyethyl; examples ofhydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy;examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxyand 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxyinclude 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples ofphenyl(1-4C)alkyl include benzyl and phenethyl; examples of(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl;examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl anddi(ethyl)carbamoyl; examples of hydroxyimino(1-4C)alkyl includehydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl;examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl,ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl;examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl,2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl includenitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples ofamino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl,1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of(1-4C)alkanesulfonamido include methanesulfonamido andethanesulfonamido; examples of (1-4C)alkylaminosulfonyl includemethylaminosulfonyl and ethylaminosulfonyl; and examples ofdi-1-4C)alkylaminosulfonyl include dimethylaminosulfonyl,diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of(1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy andpropylsulfonyloxy; examples of (1-4C)alkanoyloxy include acetoxy;examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl andethylaminocarbonyl; examples of di((1-4C)alkyl)aminocarbonyl includedimethylaminocarbonyl and diethylaminocarbonyl; examples of(3-8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyland cyclohexyl; examples of di(N-(1-4C)alkyl)aminomethylimino includedimethylaminomethylimino and diethylaminomethylimino.

Particular values for AR2 include, for example, for those AR2 containingone heteroatom, furan, pyrrole, thiophene; for those AR2 containing oneto four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine,pyridazine, 1,2,3- & 1,2,4-triazole and tetrazole; for those AR2containing one N and one O atom, oxazole, isoxazole and oxazine; forthose AR2 containing one N and one S atom, thiazole and isothiazole; forthose AR2 containing two N atoms and one S atom, 1,2,4- and1,3,4-thiadiazole.

Particular examples of AR2a include, for example, dihydropyrrole(especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially1,2,5,6-tetrahydropyrid-4-yl).

Particular examples of AR2b include, for example, tetrahydrofuran,pyrrolidine, morpholine (preferably morpholino), thiomorpholine(preferably thiomorpholino), piperazine (preferably piperazino),imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

Particular values for AR3 include, for example, bicyclic benzo-fusedsystems containing a 5- or 6-membered heteroaryl ring containing onenitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen,sulfur and nitrogen. Specific examples of such ring systems include, forexample, indole, benzofuran, benzothiophene, benzimidazole,benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline,quinoxaline, quinazoline, phthalazinc and cinnoline.

Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicyclic ringsystems containing heteroatoms in both of the rings. Specific examplesof such ring systems include, for example, purine and naphthyridine.

Further particular examples of AR3 include bicyclic heteroaryl ringsystems with at least one bridgehead nitrogen and optionally a further1-3 heteroatoms chosen from oxygen, sulfur and nitrogen. Specificexamples of such ring systems include, for example,3H-pyrrolo[1,2-a]pyrrole, pyrrolo[2,1-b]thiazole,1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole,1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole,pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole,indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine,pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole,s-triazole[1,5-a]pyridine, imidazo[1,2-c]pyrimidine,imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine,imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine,imidazo[1,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine,imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole. Other specific examplesof such ring systems include, for example, [1H]-pyrrolo[2,1-c]oxazine,[3H]-oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,1-c]oxazine andpyrido[2,1-c][1,4]oxazine. Other specific examples of 5/5-bicyclic ringsystems are imidazooxazole or imidazothiazole, in particularimidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole orimidazo[2,1-b]oxazole.

Particular examples of AR3a and AR3b include, for example, indoline,1,3,4,6,9,9a-hexahydropyrido[2,1c][1,4]oxazin-8-yl,1,2,3,5,8,8a-hexahydroimidazo[1,5a]pyridin-7-yl,1,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl,1,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl,(7aS)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl,(7aS)[5H]-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl,(7aR)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl,[3H,5H-pyrrolo[1,2-c]oxazol-6-yl,[5H]-2,3-dihydropyrrolo[1,2-c]imidazol-6-yl,[3H,5H]-pyrrolo[1,2-c]thiazol-6-yl,[3H,5H]-1,7a-dihydropyrrolo[1,2-c]thiazol-6-yl,[5H]-pyrrolo[1,2-c]imidazol-6-yl,[1H]-3,4,8,8a-tetrahydropyrrolo[2,1-c]oxazin-7-yl,[3H]-1,5,8,8a-tetrahydrooxazolo[3,4-a]pyrid-7-yl,(3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and5,8-dihydroimidazo[1,5-a]pyrid-7-yl.

Particular values for AR4 include, for example, pyrrolo[a]quinoline,2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline,1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole,5H-imidazo[2,1-a]isoindole, 1H-imidazo[3,4-a]indole,imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline,imidazo[1,5-a]quinoline and imidazo[5,1-a]isoquinoline.

The nomenclature used is that found in, for example, “HeterocyclicCompounds (Systems with bridgehead nitrogen), W. L. Mosby (IntercsiencePublishers Inc., New York), 1961, Parts 1 and 2.

Where optional substituents are listed such substitution is preferablynot geminal disubstitution unless stated otherwise. If not statedelsewhere suitable optional substituents for a particular group arethose as stated for similar groups herein.

Suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4,AR4a, CY1 and CY2 are (on an available carbon atom) up to threesubstituents independently selected from (1-4C)alkyl {optionallysubstituted by (preferably one) substituents selected independently fromhydroxy, trifluoromethyl, (1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2) (thislast substituent preferably on AR1 only), 1-4C)alkoxy,(1-4C)alkoxycarbonyl, cyano, nitro, (1-4C)alkanoylamino, —CONRvRw or—NRvRw}, trifluoromethyl, hydroxy, halo, nitro, cyano, thiol,(1-4C)alkoxy, (1-4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl,di(N—(1-4C)alkyl)aminomethylimino, carboxy, (1-4C)alkoxycarbonyl,(1-4C)alkanoyl, (1-4C)alkylSO₂amino, (2-4C)alkenyl {optionallysubstituted by carboxy or (1-4C)alkoxycarbonyl}, (2-4C)alkynyl,(1-4C)alkanoylamino, oxo(═O), thioxo(═S), (1-4C)alkanoylamino {the(1-4C)alkanoyl group being optionally substituted by hydroxy},(1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2) {the (1-4C)alkyl group beingoptionally substituted by one or more groups independently selected fromcyano, hydroxy and (1-4C)alkoxy}, —CONRvRw or —NRvRw [wherein Rv ishydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl].

Further suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b,AR4, AR4a, CY1 and CY2 (on an available carbon atom), and also on alkylgroups (unless indicated otherwise) are up to three substituentsindependently selected from trifluoromethoxy, benzoylamino, benzoyl,phenyl {optionally substituted by up to three substituents independentlyselected from halo, (1-4C)alkoxy or cyano}, furan, pyrrole, pyrazole,imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole,oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl,(1-4C)alkoxyimino(1-4C)alkyl, halo-(1-4C)alkyl, 1-4C)alkanesulfonamido,—SO₂NRvRw [wherein Rv is hydrogen or 1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl].

Preferable optional substituents on Ar2b as 1,3-dioxolan-4-yl,1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- ordisubstitution by substituents independently selected from (1-4C)alkyl(including geminal disubstitution), (1-4C)alkoxy, (1-4C)alkylthio,acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl].

Preferable optional substituents on CY1 & CY2 are mono- ordisubstitution by substituents independently selected from (1-4C)alkyl(including geminal disubstitution), hydroxy, (1-4C)alkoxy,(1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, and trifluoromethyl.

Suitable substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4aare (on an available nitrogen atom, where such substitution does notresult in quaternization) (1-4C)alkyl, (1-4C)alkanoyl {wherein the(1-4C)alkyl and (1-4C)alkanoyl groups are optionally substituted by(preferably one) substituents independently selected from cyano,hydroxy, nitro, trifluoromethyl, (1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2),(1-4C)alkoxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, —CONRvRw or—NRvRw [wherein Rv is hydrogen or 1-4C)alkyl; Rw is hydrogen or1-4C)alkyl]}, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxycarbonyl or oxo(to form an N-oxide).

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, fumarate, hydrochloride, citrate, maleate,tartrate and (less preferably) hydrobromide. Also suitable are saltsformed with phosphoric and sulfuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethylamine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine,tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such aslysine. There may be more than one cation or anion depending on thenumber of charged functions and the valency of the cations or anions. Apreferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). A prodrug may be used to alter or improvethe physical and/or pharmacokinetic profile of the parent compound andcan be formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theformula (I) or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing carboxy or hydroxygroup is, for example, a pharmaceutically-acceptable ester which ishydrolysed in the human or animal body to produce the parent acid oralcohol. Suitable pharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters for example methoxymethyl,(1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and(1-6C)alkoxycarbonyloxyethyl esters for example1-methoxycarbonyloxyethyl and may be formed at any carboxy group in thecompounds of this invention.

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing a hydroxy group orgroups includes inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters) and α-acyloxyalkyl ethers and relatedcompounds which as a result of the in-vivo hydrolysis of the esterbreakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkylethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Aselection of in-vivo hydrolysable ester forming groups for hydroxyinclude (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyland phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonateesters), di-(1-4C)alkylcarbamoyl andN—(di-(1-4C)alkylaminoethyl)-N—(1-4C)alkylcarbamoyl (to givecarbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples ofsubstituents on benzoyl include chloromethyl or aminomethyl,1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and morpholino orpiperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring.

Certain suitable in-vivo hydrolysable esters of a compound of theformula (I) are described within the definitions listed in thisspecification, for example esters described by the definition (Rc2d),and some groups within (Rc2c). Suitable in-vivo hydrolysable esters of acompound of the formula (I) are described as follows. For example, a1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or apyrophosphate of formula (PD2):

Particularly interesting are such cyclised pro-drugs when the 1,2-diolis on a (1-4C)alkyl chain linked to a carbonyl group in a substituent offormula Rc borne by a nitrogen atom in (TC4). Esters of compounds offormula (I) wherein the HO— function/s in (PD1) and (PD2) are protectedby (1-4C)alkyl, phenyl or benzyl are useful intermediates for thepreparation of such pro-drugs.

Further in-vivo hydrolysable esters include phosporamidic esters, andalso compounds of formula (I) in which any free hydroxy groupindependently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0)ester of the formula (PD3):

Useful intermediates for the preparation of such esters includecompounds containing a group/s of formula (PD3) in which either or bothof the —OH groups in (PD3) is independently protected by (1-4C)alkyl(such compounds also being interesting compounds in their own night),phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionallysubstituted by 1 or 2 groups independently selected from (1-4C)alkyl,nitro, halo and (1-4C)alkoxy).

Thus, prodrugs contain in groups such as (PD1), (PD2) and (PD3) may beprepared by reaction of a compound of formula (I) containing suitablehydroxy group/s with a suitably protected phosphorylating agent (forexample, containing a chloro or dialkylamino leaving group), followed byoxidation (if necessary) and deprotection.

When a compound of formula (I) contains a number of free hydroxy group,those groups not being converted into a prodrug functionality may beprotected (for example, using a t-butyl-dimethylsilyl group), and laterdeprotected. Also, enzymatic methods may be used to selectivelyphosphorylate or dephosphorylate alcohol functionalities.

Other interesting in-vivo hydrolysable esters include, for example,those in which Rc is defined by, for example, R¹⁴C(O)O(1-6C)alkyl-CO—(wherein R¹⁴ is for example, benzyloxy-(1-4C)alkyl, or phenyl). Suitablesubstituents on a phenyl group in such esters include, for example,4-(1-4C)piperazino-(1-4C)alkyl, piperazino-(1-4C)alkyl andmorpholino-(1-4C)alkyl.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable estermay be formed this is achieved by conventional techniques. Thus, forexample, compounds containing a group of formula (PD1), (PD2) and/or(PD3) may ionise (partially or fully) to form salts with an appropriatenumber of counter-ions. Thus, by way of example, if an in-vivohydrolysable ester prodrug of a compound of formula (I) contains two(PD3) groups, there are four HO—P— functionalities present in theoverall molecule, each of which may form an appropriate salt (i.e. theoverall molecule may form, for example, a mono-, di-, tri- ortetra-sodium salt).

The compounds of the present invention have a chiral centre at the C-5position of the oxazolidinone ring. The pharmaceutically activeenantiomer is of the formula (IA):

The present invention includes the pure enantiomer depicted above ormixtures of the 5R and 5S enantiomers, for example a racemic mixture. Ifa mixture of enantiomers is used, a larger amount (depending upon theratio of the enantiomers) will be required to achieve the same effect asthe same weight of the pharmaceutically active enantiomer. For theavoidance of doubt the enantiomer depicted above is the 5R enantiomer.

Furthermore, some compounds of the formula (I) may have other chiralcentres. It is to be understood that the invention encompasses all suchoptical and diastereo-isomers, and racemic mixtures, that possessantibacterial activity. It is well known in the art how to prepareoptically-active forms (for example by resolution of the racemic form byrecrystallisation techniques, by chiral synthesis, by enzymaticresolution, by biotransformation or by chromatographic separation) andhow to determine antibacterial activity as described hereinafter.

The invention relates to all tautomeric forms of the compounds of theformula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)may exhibit polymorphism, and that the invention encompasses all suchforms which possess antibacterial activity.

As stated before, we have discovered a range of compounds that have goodactivity against a broad range of Gram-positive pathogens includingorganisms known to be resistant to most commonly used antibiotics.Physical and/or pharmacokinetic properties, for example increasedstability to mammalian peptidase metabolism and a favourabletoxicological profile are important features. The following compoundspossess particularly favourable physical and/or pharmacokineticproperties and are preferred.

Particularly preferred compounds of the invention comprise a compound offormula (I) or of formula (IP), or a pharmaceutically-acceptable salt oran in-vivo hydrolysable ester thereof, wherein the substituents Q, X,HET, T and other substituents mentioned above have values disclosedhereinbefore, or any of the following values (which may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore or hereinafter):

Preferably Q is selected from Q1, Q2, Q4, Q6 and Q9; especially Q1, Q2and Q9; more particularly Q1 and Q2; and most preferably Q is Q1.

Preferably T is selected from (TAf), (TDb) or (TC); especially groups(TCb) and (TCc); more particularly (TC2), (TC3) and (TC4); and mostpreferably (TC5), (TC7) or (TC9), and most particularly (TC5).Especially preferred is each of these values of T when present in Q1 andQ2, particularly in Q1.

Preferable values for other substituents (which may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore or hereinafter) are:

(a) Preferably X is —O—;

(a1) In another aspect X is —S—;

(b) Preferably HET is pyrazole, imidazole, oxazoic, isoxazole,1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, isothiazole or1,2,5-thiadiazole. Yet more preferably HET is pyrazol-3-yl,imidazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl,1,3,4-oxadiazol-2-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl;

(b1) Especially preferred is HET as isoxazole (optionally substituted asdisclosed hereinbefore), particularly isoxazol-3-yl;

(b2) In another embodiment HET is as defined hereinbefore orhereinafter, but excluding thiazole and thiadiazole; and in anotherembodiment HET is as defined hereinbefore or hereinafter, but excludingisothiazole and thiadiazole;

(b3) Preferably HET is unsubstituted;

(c) Preferably Rp is hydrogen;

(d) Preferably Rp1 and Rp2 are independently selected from hydrogen,(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl,(1-4C)alkoxymethyl or carbamoyl;

(e) Most preferably Rp1 and Rp2 are hydrogen;

(f) Preferably one of R² and R³ is hydrogen and the other fluoro;

(g) In another aspect both R² and R³ are fluoro;

(h) Preferably >A—B— is of the formula >C═CH— (i.e. Rr is preferablyhydrogen) or >N—CH₂—;

(i) Preferably D is —O— or >NRcp;

(j) Preferably Rcp is AR, R^(13p)CO—, R^(13p)SO₂—, R^(13p)CS—;

(k) More preferably Rcp is AR (most preferably benzyl, pyrimidyl,pyridinyl, pyridazinyl or pyrazinyl) or R^(13p)CO— (especiallyR^(13p)CO—);

(l) Preferably AR is 5- or 6-membered heteroaryl; more preferably AR is6-membered heteroaryl, such as pyridinyl;

(m) Preferred substituents for phenyl and carbon atoms in heteroaryl(mono- and bicyclic) ring systems in AR, R^(14p) and Ri include halo,(1-4C)alkyl, hydroxy, nitro, amino, cyano, (1-4C)alkylS(O)_(p)— and(1-4C)alkoxy;

(n) Preferably the optionally substituted ring systems in AR, R^(14p)and Ri are unsubstituted;

(n1) In another embodiment in the definition of R^(13p) in (PC) ofembodiment (IP), 1,3-dioxolan-4-yl and 1,4-dioxan-2-yl are excluded.

(o) Preferably R^(13p) is 1-4C)alkoxycarbonyl, hydroxy(1-4C)alkyl,1-4C)alkyl (optionally substituted by one or two hydroxy groups, or byan (1-4C)alkanoyl group), (1-4C)alkylamino, dimethylamino(1-4C)alkyl,(1-4C)alkoxymethyl, (1-4C)alkanoylmethyl, (1-4C)alkanoyloxy(1-4C)alkyl,1-5C)alkoxy or 2-cyanoethyl;

(p) More preferably R^(13p) is 1,2-dihydroxyethyl,1,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-1-yl, methoxycarbonyl,hydroxymethyl, methyl, methylamino, dimethylaminomethyl, methoxymethyl,acetoxymethyl, methoxy, methylthio, naphthyl, tert-butoxy or2-cyanoethyl;

(p1) Yet more preferably R^(13p) is 1,2-dihydroxyethyl,1,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-1-yl;

(q) Preferred optional substituents for (1-10C)alkyl in R^(14p) arehydroxy, cyano, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino,1-4C)alkylS(O)_(p)— (wherein p is 1 or 2), carboxy,(1-4C)alkoxycarbonyl, (1-4C)alkoxy, piperazino or morpholino;

(r) Preferred optional substituents for (1-6C)alkyl in R^(15p) arehydroxy, (1-4C)alkoxy, cyano, amino, (1-4C)alkylamino,di((1-2C)alkyl)amino, (1-4C)alkylS(O)_(p)— (wherein p is 1 or 2);

(s) Preferably 5- or 6-membered heteroaryl in R^(14p) is pyridinyl orimidazol-1-yl;

(t) Preferably R^(15p) is (1-6C)alkyl; most preferably R^(15p) istert-butyl or methyl;

(u) Preferably R^(17p) is cyano or fluoro;

(v) Preferably R^(16p) is hydrogen;

(w) Preferably CY is naphthoxy, especially naphth-1-oxy or naphth-2-oxy.

Where preferable values are given for substituents in a compound offormula (IP), the corresponding substituents in a compound of formula(I) have the same preferable values (thus, for example, R¹³ and Rc informula (I) correspond with Rcp and R^(13p) in formula (IP), andsimilarly for groups D and G). For compounds of formula (I) preferredvalues for Rc are those in group (Rc2). The preferred values for R^(13p)listed above for compounds of formula (IP) are also preferred values forR¹³ in compounds of formula (I). In the definition of (Rc2c) the AR2a,AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups arepreferably excluded.

In another aspect, HET is a C-linked 5-membered heteroaryl ringcontaining 2 or 3 heteratoms independently selected from N, O and S(with the proviso that there are no O—O, O—S, S—S or N—S bonds), whichring is optionally substituted on any available C atom (provided thatwhen a N atom is adjacent to the X-link, there is no substitution on anyC atom that is adjacent to this N atom) by 1 or 2 substituentsindependently selected from (1-4C)alkyl, amino, (1-4C)alkylamino,(1-4C)alkoxy and halogen, and/or on an available N atom (provided thatthe ring is not thereby quaternised), by (1-4C)alkyl.

In another aspect, HET is selected from the formulae (HET1) to (HET3)below:

wherein A₂ is carbon or nitrogen and B₂ is O, S or N (with a maximum of3 hetero atoms per ring), with carbon or nitrogen ring atoms beingoptionally substituted as described for HET hereinbefore (preferablywith no substitution on any carbon atom that is adjacent to thespecified N atom).

In another embodiment HET is as defined herein and also optionallysubstituted on an available suitable C atom by (1-4C)alkoxycarbonyl.

The above HET definitions are especially preferred in embodiment (IP),and with preferable value (n1) of R^(13p).

Especially preferred compounds of the present invention are of theformula (IB):

wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or1,2,5-thiadiazol-3-yl; R² and R³ are independently hydrogen or fluoro;and Rp1 and Rp2 are independently hydrogen, hydroxy, bromo, (1-4C)alkyl,carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl orcarbamoyl; or pharmaceutically-acceptable salts thereof.

Further especially preferred compounds of the invention are of theformula (IB) wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl,isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R² and R³ are independentlyhydrogen or fluoro; and Rp1 and Rp2 are independently hydrogen,AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl-(1-4C)alkyl,naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine,pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole orthiophene); or pharmaceutically-acceptable salts thereof.

Of the above especially preferred compounds of the invention of theformula (IB), particularly preferred compounds are those wherein Rp1 andRp2 arc hydrogen are particularly preferred.

Further, especially preferred compounds of the invention are of theformula (IC):

wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or1,2,5-thiadiazol-3-yl; R² and R³ are independently hydrogen or fluoro;Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl(wherein AR is phenyl, phenyl-(1-4C)alkyl, naphthyl, furan, pyrrole,pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole or thiophene), (1-4C)alkyl,carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl orcarbamoyl and Rcp is cyano, pyrimidin-2-yl, 2-cyanoethenyl,2-cyano-2-((1-4C)alkyl)ethenyl or Rcp is of the formula R^(13p)CO—,R^(13p)SO₂— or R^(13p)CS— (wherein R^(13p) is hydrogen, (1-5C)alkyl[optionally substituted by one or more groups each independentlyselected from hydroxy and amino, or optionally monosubstituted by(1-4C)alkoxy, (1-4C)alkylS(O)_(q)—, (1-4C)alkylamino, (1-4C)alkanoyl,naphthoxy, (2-6C)alkanoylamino or (1-4C)alkylS(O)_(p)NH— wherein p is 1or 2 and q is 0, 1 or 2], imidazole, triazole, pyrimidine, pyridazine,pyridine, isoxazole, oxazole, isothiazole, thiazole, pyridoimidazole,pyrimidoimidazole, quinoxaline, quinazoline, phthalazine, cinnoline ornaphthyridine, or R^(13p) is of the formula R^(14p)C(O)O(1-6C)alkylwherein R^(14p) is (1-6C)alkyl), or Rcp is of the formula RfC(═O)C(═O)—wherein Rf is (1-6C)alkoxy; or pharmaceutically-acceptable saltsthereof.

Of the above especially preferred compounds of the invention of theformula (IC), those wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl,isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R² and R³ are independentlyhydrogen or fluoro; Rp1 and Rp2 are independently hydrogen, AR-oxymethylor AR-thiomethyl (wherein AR is phenyl, phenyl-(1-4C)alkyl, naphthyl,furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine,pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene),(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl,(1-4C)alkoxymethyl or carbamoyl and Rcp is cyano, pyrimidin-2-yl,2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl or Rcp is of the formulaR^(13p)CO—, R^(13p)SO₂— or R^(13p)CS— (wherein R^(13p) is hydrogen,1-5C)alkyl [optionally substituted by one or more groups eachindependently selected from hydroxy and amino, or optionallymonosubstituted by (1-4C)alkoxy, (1-4C)alkylS(O)_(q), (1-4C)alkylamino,(1-4C)alkanoyl, (2-6C)alkanoylamino or (1-4C)alkylS(O)_(p)NH— wherein pis 1 or 2 and q is 0, 1 or 2], pyridine, or R^(13p) is of the formulaR^(14p)C(O)O(1-6C)alkyl wherein R^(14p) is (1-6C)alkyl), or Rcp is ofthe formula RfC(═O)C(═O)— wherein Rf is (1-6C)alkoxy; orpharmaceutically-acceptable salts thereof are further preferred.

Of the above especially preferred compounds of the invention of theformula (IC), particularly preferred compounds are those wherein HET isisoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or1,2,5-thiadiazol-3-yl; R² and R³ are independently hydrogen or fluoro;Rp1 and Rp2 are hydrogen, and Rcp is pyridin-2-yl (optionallysubstituted with cyano) or Rcp is of the formula R^(13p)CO— (whereinR^(13p) is hydrogen, 1,3-dioxolan-4-yl (optionally disubstituted with(1-4C)alkyl) or (1-5C)alkyl [optionally substituted by one or morehydroxy groups] or R^(13p) is of the formula R^(14p)C(O)O(1-6C)alkylwherein R^(14p) is (1-6C)alkyl)); or pharmaceutically-acceptable saltsthereof.

Of the above especially preferred compounds of the invention of theformula (IC), particularly preferred compounds are those wherein Rcp isof the formula R^(13p)CO— (wherein R^(13p) is hydrogen,1,3-dioxolan-4-yl (optionally disubstituted with (1-4C)alkyl) or(1-5C)alkyl [substituted by two hydroxy groups]; orpharmaceutically-acceptable salts thereof.

In another aspect of the invention all of the compounds of formula (IB)or (IC) described above are further preferred when HET is isoxazol-3-yl,isothiazol-3-yl or 1,2,5-thiadiazol-3-yl.

In yet another aspect the invention relates to all of the compounds offormula (IB) or (IC) described above wherein HET is isoxazol-3-yl or1,2,4-oxadiazol-3yl.

In yet another aspect the invention relates to all of the compounds offormula (IB) or (IC) described above wherein HET is isoxazol-3-yl.

In another aspect of the invention there are provided preferredcompounds of the formula (IP) wherein —X—HET is isoxazol-3-yloxy,1,2,4-oxadiazol-3-yloxy, isothiazol-3-yloxy,1,2,5-thiadiazol-3-yloxy; >A—B— is >N—CH₂— and D is NRcp wherein Rcp isa 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms asthe only ring heteroatoms, linked via a ring carbon atom and optionallysubstituted on a ring carbon atom by one, two or three substituentsindependently selected from (1-4C)alkyl, halo, trifluoromethyl,(1-4C)alkyl S(O)_(q)— (wherein q is 0, 1 or 2), 1-4C)alkylS(O)₂amino,(1-4C)alkanoylamino, carboxy, hydroxy, amino, (1-4C)alkylamino,di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, carbamoyl,N—(1-4C)alkylcarbamoyl, di-(N—(1-4C)alkyl)carbamoyl, (1-4C)alkoxy, cyanoor nitro, or pharmaceutically-acceptable salts thereof.

In all of the above aspects and preferred compounds of formula (IB) or(IC), in-vivo hydrolysable esters are preferred, especially phosphorylesters (as defined by formula (PD3) with npd as 1).

In all of the above definitions the preferred compounds are as shown informula (IA), i.e. the pharmaceutically active (5(R)) enantiomer.

Particular compounds of the present invention include the following (andthe individual isomers where a mixture of isomers is possible):

5(R)-Isoxazol-3-yloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;

5(R)-(5-Methylisoxazol-3-yloxymethyl)-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R,S)-ylcarbonyl)-5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(4-(5-cyanopyrid-2-yl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one;

5(R)-Isothiazol-3-yloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;

5(R)-(1,2,5-Thiadiazol-3-yloxymethyl)-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;or pharmaceutically-acceptable salts thereof.

Of the above compounds, especially preferred is (and the individualisomers thereof):

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one;or pharmaceutically-acceptable salts or in-vivo hydrolysable estersthereof.

Also preferred are the 3-fluorophenyl analogues of the particular3,5-difluoro compounds mentioned above.

Other preferred Examples if not already specifically mentioned areExample Nos. 1, 2, 7, 14, 48, 148, 151 and 23.

Also preferred is the compound (and the individual isomers thereof):

5(R)-Isothiazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)-oxazolidin-2-one;or pharmaceutically-acceptable salts or in-vivo hydrolysable estersthereof.

Most particularly preferred Examples are Example Nos. 12, 18, 19, 20, 21and 22 or pharmaceutically-acceptable salts. In-vivo hydrolysable estersof Examples 12 and 18 are preferred, especially phosphoryl esters.

Thus, preferred are the compounds, or pharmaceutically-acceptable saltsthereof:

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.

Also preferred are the compounds, or pharmaceutically-acceptable saltsthereof:

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.

Also preferred are the compounds, or pharmaceutically-acceptable saltsthereof:

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-hydroxy-2(S)-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one;

5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-hydroxy-2(S)-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.

Suitable pharmaceutically-acceptable salts of the last two namedcompounds and of Example Nos. 19, 20, 21 and 22 are the mono- anddi-salts of the mono-phosphoryl ester compounds and the mono-, di-, tri-and tetra-salts of the di-phosphoryl ester compounds (Examples 19 and21). Particularly preferred salts are the sodium salts.

Process Section:

In a further aspect the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically-acceptablesalt or an in-vivo hydrolysable ester thereof. It will be appreciatedthat during certain of the following processes certain substituents mayrequire protection to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method as described in the literature or knownto the skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with minimum disturbance of groups elsewhere in themolecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Examples of the use of resins as a protecting group are illustrated inExamples 135 & 136 herein.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

A compound of the formula (I), or a pharmaceutically-acceptable salt oran in vivo hydrolysable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a compound of theformula (I), or a pharmaceutically-acceptable salt or an in vivohydrolysable ester thereof, are provided as a further feature of theinvention and are illustrated by the following representative examples.Necessary starting materials may be obtained by standard procedures oforganic chemistry (see, for example, Advanced Organic Chemistry(Wiley-Interscience), Jerry March). The preparation of such startingmaterials is described within the accompanying non-limiting Examples.Alternatively, necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist. Information on the preparation of necessary startingmaterials or related compounds (which may be adapted to form necessarystarting materials) may also be found in the following Patent andApplication Publications, the contents of the relevant process sectionsof which are hereby incorporated herein by reference:

WO99/02525; WO98/54161; WO97/37980; WO97/30981 (& U.S. Pat. No.5,736,545); WO97/21708 (& U.S. Pat. No. 5,719,154); WO97/10223;WO97/09328; WO96/35691; WO96/23788; WO96/15130; WO96/13502; WO95/25106(& U.S. Pat. No. 5,668,286); WO95/14684 (& U.S. Pat. No. 5,652,238);WO95/07271 (& U.S. Pat. No. 5,688,792); WO94/13649; WO94/01110;WO93/23384 (& U.S. Pat. No. 5,547,950 & U.S. Pat. No. 5,700,799);WO93/09103 (& U.S. Pat. No. 5,565,571, U.S. Pat. No. 5,654,428, U.S.Pat. No. 5,654,435, U.S. Pat. No. 5,756,732 & U.S. Pat. No. 5,801,246);U.S. Pat. No. 5,231,188; U.S. Pat. No. 5,247,090; U.S. Pat. No.5,523,403; WO97/27188; WO97/30995; WO97/31917; WO98/01447; WO98/01446;WO99/10342; WO99/10343; WO99/11642; European Patent Application Nos.0,359,418 and 0,609,905; 0,693,491 A1 (& U.S. Pat. No. 5,698,574);0,694,543 A1 (& AU 24985/95); 0,694,544 A1 (& CA 2,154,024); 0,697,412A1 (& U.S. Pat. No. 5,529,998); 0,738,726 A1 (& AU 50735/96); 0,785,201A1 (& AU 10123/97); German Patent Application Nos. DE 195 14 313 A1 (&U.S. Pat. No. 5,529,998); DE 196 01 264 A1 (& AU 10098/97); DE 196 01265 A1 (& AU 10097/97); DE 196 04 223 A1 (& AU 12516/97); DE 196 49 095A1 (& AU 12517/97).

The following Patent and Application Publications may also provideuseful information and the contents of the relevant process sections arehereby incorporated herein by reference:

FR 2458547; FR 2500450(& GB 2094299, GB 2141716 & U.S. Pat. No.4,476,136); DE 2923295 (& GB 2028306, GB 2054575, U.S. Pat. No.4,287,351, U.S. Pat. No. 4,348,393, U.S. Pat. No. 4,413,001, U.S. Pat.No. 4,435,415 & U.S. Pat. No. 4,526,786), DE 3017499 (& GB 2053196, U.S.Pat. No. 4,346,102 & U.S. Pat. No. 4,372,967); U.S. Pat. No. 4,705,799;European Patent Application Nos. 0,312,000; 0,127,902; 0,184,170;0,352,781; 0,316,594;

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references toobtain necessary starting materials.

Thus, the present invention also provides that the compounds of theformulae (I) and pharmaceutically-acceptable salts and in vivohydrolysable esters thereof, can be prepared by a process (a) to (i) asfollows (wherein the variables are as defined above unless otherwisestated):

(a) by modifying a substituent in or introducing a substituent intoanother compound of formula (I);

(b) by reaction of a compound of formula (II)

wherein Yp is hydroxy with a compound of the formula (b1) HET—OH or (b2)HET—Lg, wherein Lg is a suitable leaving group;

(c) by reaction of a compound of formula (II) wherein Yp is a leavinggroup, for example halogen, mesylate or tosylate, with a metal alkoxidecompound of the formula HET—OM where M is an alkali metal, or anothermetal, such as silver, known to promote O-alkylation;

(d) by reaction of a compound of the formula Q—Zp wherein Zp is anisocyanate or amine group with an epoxide of the formulaCH₂(O)CH—CH₂O—HET;

(e) when X is —S— by a process analogous to process (c) wherein (e1) ametal thioxide compound of the formula HET—SM where M is an alkalimetal, or another metal, such as silver, known to promote S-alkylation;or (e2) alternatively by a process analogous to process (c) using HET—SHand a compound of formula (II) in which Yp is a suitable leaving group;

(f) when X is —SO— or —SO₂— by oxidation of a compound wherein X is —S—;

(g) by conversion to a non-quaternary compound of a compound of formula(I) in which the ring HET bears a quaternary nitrogen;

(h) when HET is an isoxazole ring by reaction of a compound of theformula (II) in which Yp is —O—CH═N—OH with an acetylene;

(i) by reaction of a urethane compound of formula (III) with a compoundof formula (IV)

wherein R²¹ is (1-6C)alkyl or benzyl; and thereafter if necessary

(i) removing any protecting groups; (ii) forming apharmaceutically-acceptable salt; (iii) forming an in vivo hydrolysableester.

General guidance on reaction conditions and reagents may be obtained inAdvanced Organic Chemistry, 4^(th) Edition, Jerry March (publisher: J.Wiley & Sons), 1992. Necessary starting materials may be obtained bystandard procedures of organic chemistry, such as described in thisprocess section, in the Examples section or by analogous procedureswithin the ordinary skill of an organic chemist. Certain references arealso provided (see above) which describe the preparation of certainsuitable starting materials, for particular example see InternationalPatent Application Publication No. WO 97/37980, the contents of whichare incorporated here by reference. Processes analogous to thosedescribed in the references may also be used by the ordinary organicchemist to obtain necessary starting materials.

(a) Methods for converting substituents into other substituents areknown in the art. For example an alkylthio group may be oxidised to analkylsulfinyl or alkylsulfonyl group, a cyano group reduced to an aminogroup, a nitro group reduced to an amino group, a hydroxy groupalkylated to a methoxy group, a hydroxy group thiomethylated to anarylthiomethyl or a heteroarylthiomethyl group (see, for example,Tet.Lett., 585, 1972), a carbonyl group converted to a thiocarbonylgroup (eg. using Lawsson's reagent) or a bromo group converted to analkylthio group. It is also possible to convert one Rc group intoanother Rc group as a final step in the preparation of a compound of theformula (I).

One compound of formula (I) may be converted into another compound offormula (I) by reacting a compound of formula (I) in which T is halowith a suitable compound to form another value of T. Thus, for example,T as halo may be displaced by suitable vinyl, aromatic, tropolone andnitrogen-linked systems as T by reaction using known Pd(0) couplingtechniques.

Further examples of converting substituents into other substituents arecontained in the accompanying non-limiting Examples.

(b1) When HET—OH is used reaction (b1) is performed under Mitsunobuconditions, for example, in the presence of tri-n-butylphosphine anddiethyl azodicarboxylate (DEAD) in an organic solvent such as THF, andin the temperature range 0° C.-60° C., but preferably at ambienttemperature. Details of Mitsunobu reactions are contained in Tet.Letts., 31, 699, (1990); The Mitsunobu Reaction, D. L. Hughes, OrganicReactions, 1992, Vol. 42, 335-656 and Progress in the MitsunobuReaction, D. L. Hughes, Organic Preparations and ProceduresInternational, 1996, Vol. 28, 127-164.

(b2) When HET—Lg is used reaction (b2) is performed using a suitablyreactive HET and under basic conditions (using a base such as1,8-diazabicyclo[5,4,0]undec-7-ene) which are sufficiently mild not todestroy the oxazolidinone ring structure. The skilled organic chemistwill appreciate which suitable leaving group Lg (such as chloro orbromo) and reaction conditions to use.

Compounds of the formula (II) wherein Yp is hydroxy may be obtained byreacting a compound of the formula (III) with a compound of formula (V):

wherein R²¹ is (1-6C)alkyl or benzyl and R²² is (1-4C)alkyl orS(O)_(q)(1-4C)alkyl where q is 0, 1 or 2. Preferably R²² is (1-4C)alkyl.

Compounds of the formula (II), (III) and (V) may be prepared by theskilled chemist, for example as described in International PatentApplication Publication Nos. WO95/07271, WO97/27188, WO 97/30995, WO98/01446 and WO 98/01446, the contents of which are hereby incorporatedby reference, and by analogous processes.

If not commercially available, compounds of the formula HET—OH andHET—Lg may be prepared by procedures which are selected from standardchemical techniques, techniques which are analogous to the synthesis ofknown, structurally similar compounds, or techniques which are analogousto the procedures described in the Examples. For example, standardchemical techniques are as described in Houben Weyl, Methoden derOrganische Chemie, E8a, Pt.I (1993), 45-225, B. J. Wakefield (forisoxazoles) and E8c, Pt.I (1994) 409-525, U. Kraatz (for1,2,4-oxadiazoles). Also, for example, 3-hydroxyisoxazole may beprepared by cyclisation of CH≡C—CO—NHOH (prepared fromCH≡C—CO—O—(-4C)alkyl) as described in Chem.Pharm.Bull.Japan, 14, 92,(1966).

(c) & (e) Reactions (c) and (e) are performed conveniently at atemperature in the range 25-60° C. in a solvent such as MAP or DMF.

A compound of the formula (II) wherein Yp is fluoro may be prepared byreacting a compound of the formula (II) wherein Yp is hydroxy (hiydroxycompound) with a fluorinating agent such as diethylaminosulfurtrifluoride in an organic solvent such as dichloromethane in thetemperature range of 0° C. to ambient temperature.

When Yp is chloro, the compound of the formula (II) may be formed byreacting the hydroxy compound with a chlorinating agent. For example, byreacting the hydroxy compound with thionyl chloride, in a temperaturerange of ambient temperature to reflux, optionally in a chlorinatedsolvent such as dichloromethane or by reacting the hydroxy compound withcarbon tetrachloride/triphenyl phosphine in dichloromethane, in atemperature range of 0° C. to ambient temperature. A compound of theformula (II) wherein Yp is chloro or iodo may also be prepared from acompound of the formula (II) wherein Yp is mesyl ate or tosylate, byreacting the latter compound with lithium chloride or lithium iodide andcrown ether, in a suitable organic solvent such as THF, in a temperaturerange of ambient temperature to reflux

When Yp is (1-4C)alkanesulfonyloxy or tosylate the compound (II) may beprepared by reacting the hydroxy compound with (1-4C)alkanesulfonylchloride or tosyl chloride in the presence of a mild base such astriethylamine or pyridine.

Compounds of the formula HET—OM and HET—SM may be prepared by theskilled chemist from the corresponding HET—OH or HET—SH compound, usinga suitable base, such as sodium hydride, silver carbonate, sodiumcarbonate or an alkoxide.

When X is —S— and a process is used that is analogous to process (c) butusing HET—SH and a compound of formula (II) in which Yp is a suitableleaving group, a suitable leaving group is, for example, mesylate and asuitable base for the reaction is a base such as1,8-diazabicyclo[5,4,0]undec-7-ene (see for example, Example 153).

(d) Reaction (d) is performed under conditions analogous to thosedescribed in the following references which disclose how suitable andanalogous starting materials may be obtained.

Compounds of the formula Q—Zp wherein Zp is an isocyanate may beprepared by the skilled chemist, for example by analogous processes tothose described in Walter A. Gregory et al in J.Med.Chem. 1990, 33,2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165.Compounds of the formula Q—Zp wherein Zp is a urethane (see process (i))may be prepared by the skilled chemist, for example by analogousprocesses to those described in International Patent ApplicationPublication Nos. WO 97/30995 and WO 97/37980.

A similar reaction to reaction (d) may be performed in which Q—Zpwherein Zp is a amine group is reacted with the epoxide (optionally inthe presence of an organic base), and the product is reacted with, forexample, phosgene to form the oxazolidinone ring. Such reactions and thepreparation of starting materials in within the skill of the ordinarychemist with reference to the above-cited documents disclosing analogousreactions and preparations.

Epoxides of the formula CH₂(O)CH—CH₂O—HET may be prepared from thecorresponding CH₂═CH—CH₂—O—HET compound. Certain such epoxide and alkeneintermediates are novel and are provided as a further feature of theinvention. For example, when HET is isoxazol-3-yl,3-(2,3-oxiranepropyloxy)isoxazole may be prepared from3-allyloxyisoxazole. Asymmetric epoxidation may be used to give thedesired optical isomer.

(f) When X is —SO— or —SO₂— the oxidation of a compound wherein X is —S—may be achieved by oxidising with standard reagents known in the art forthe oxidation of a thio group to a sulfinyl or sulfonyl group. Forexample, a thio group may be oxidised to a sulfinyl group with a peracidsuch as m-chloroperoxybenzoic acid and oxidising agents such aspotassium permanganate can be used to convert a thio group to a sulfonylgroup.

(g) The conversion to a non-quaternary compound of a compound of formula(I) in which the ring HET bears a quaternary nitrogen may be achievedunder thermal conditions suitable to achieve elimination of thequaternary group (for example, a methyl group will be eliminated as amethyl halide).

A compound of formula (I) in which the ring HET bears a quaternarynitrogen may be prepared in a similar manner to the conditions describedfor reaction (c), although a suitably quaternised HET compound,substituted in the alpha position next to nitrogen by a leaving group(such as halogen), and a compound of the formula (II) in which Yp is —OHor —SH, is used. Such starting materials are readily prepared by theordinary organic chemist.

A compound of formula (I) in which the ring HET bears a quaternarynitrogen may also be prepared in a similar manner to the conditionsdescribed in Chem.Pharm.Bull.Japan, 27, 2415-2423, (1979), by reactionof an N-alkylated HET—OH or HET—SH compound in the keto-form (with theketo (oxo or thioxo) group in the alpha position next to nitrogen) witha compound of formula (II) in which Yp is a leaving group such asmesylate.

(h) When the HET ring is isoxazole it may be built up as a final stepfrom a compound of the formula (II) in which Yp is —O—CH═N—OH byreaction under standard conditions with an acetylene (see for example,Acta Chem. Scand 47, 1004, 1993).

(i) A compound of formula (III) is reacted with a compound of formula(IV) using similar conditions to those for reaction of a compound of theformula (III) with a compound of formula (V) described above. If notcommercially available, the preparation of suitable starting materialsof formulae (III) and (IV) is as described above, or by using analogousprocesses.

The removal of any protecting groups, the formation of apharmaceutically-acceptable salt and/or the formation of an in vivohydrolysable ester are within the skill of an ordinary organic chemistusing standard techniques. Furthermore, details on the these steps, forexample the preparation of in-vivo hydrolysable ester prodrugs has beenprovided in the section above on such esters, and in certain of thefollowing non-limiting Examples.

When an optically active form of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material (formed, for example, byasymmetric induction of a suitable reaction step), or by resolution of aracemic form of the compound or intermediate using a standard procedure,or by chromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically-acceptable salt, orin-vivo hydrolysable ester thereof for use in a method of treatment ofthe human or animal body by therapy.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof.

The invention also provides a compound of the formula (I), or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof,for use as a medicament; and the use of a compound of the formula (I) ofthe present invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof, in the manufacture of a medicament for usein the production of an antibacterial effect in a warm blooded animal,such as man.

In order to use a compound of the formula (I), an in-vivo hydrolysableester or a pharmaceutically-acceptable salt thereof, including apharmaceutically-acceptable salt of an in-vivo hydrolysable ester,(hereinafter in this section relating to pharmaceutical composition “acompound of this invention”) for the therapeutic (includingprophylactic) treatment of mammals including humans, in particular intreating infection, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula(I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable saltthereof, including a pharmaceutically-acceptable salt of an in-vivohydrolysable ester, and a pharmaceutically-acceptable diluent orcarrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, rectal or parenteral administration. For thesepurposes the compounds of this invention may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions or suspensions, (lipid) emulsions, dispersiblepowders, suppositories, ointments, creams, aerosols (or sprays), dropsand sterile injectable aqueous or oily solutions or suspensions.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain or be co-administered(simultaneously, sequentially or separately) with one or more knowndrugs selected from other clinically useful antibacterial agents (forexample, β-lactams or aminoglycosides) and/or other anti-infectiveagents (for example, an antifungal triazole or amphotericin). These mayinclude carbapenems, for example meropenem or imipenem, to broaden thetherapeutic effectiveness. Compounds of this invention may also containor be co-administered with bactericidal/permeability-increasing protein(BPI) products or efflux pump inhibitors to improve activity againstgram negative bacteria and bacteria resistant to antimicrobial agents.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 1 mg and 1 g of a compound of thisinvention, preferably between 100 mg and 1 g of a compound. Especiallypreferred is a tablet or capsule which contains between 50 mg and 800 mgof a compound of this invention, particularly in the range 100 mg to 500mg.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection, forexample an injection which contains between 0.1% w/v and 50% w/v(between 1 mg/ml and 500 mg/ml) of a compound of this invention.

Each patient may receive, for example, a daily intravenous, subcutaneousor intramuscular dose of 0.5 mgkg⁻¹ to 20 mgkg⁻¹ of a compound of thisinvention, the composition being administered 1 to 4 times per day. Inanother embodiment a daily dose of 5 mgkg⁻¹ to 20 mgkg⁻¹ of a compoundof this invention is administered. The intravenous, subcutaneous andintramuscular dose may be given by means of a bolus injection.Alternatively the intravenous dose may be given by continuous infusionover a period of time. Alternatively each patient may receive a dailyoral dose which may be approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day.

A pharmaceutical composition to be dosed intravenously may containadvantageously (for example to enhance stability) a suitablebactericide, antioxidant or reducing agent, or a suitable sequesteringagent.

In the above other, pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

Antibacterial Activity:

The pharmaceutically-acceptable compounds of the present invention areuseful antibacterial agents having a good spectrum of activity in vitroagainst standard Gram-positive organisms, which are used to screen foractivity against pathogenic bacteria. Notably, thepharmaceutically-acceptable compounds of the present invention showactivity against enterococci, pneumococci and methicillin resistantstrains of S.aureus and coagulase negative staphylococci. Theantibacterial spectrum and potency of a particular compound may bedetermined in a standard test system.

The (antibacterial) properties of the compounds of the invention mayalso be demonstrated and assessed in-vivo in conventional tests, forexample by oral and/or intravenous dosing of a compound to awarm-blooded mammal using standard techniques.

The following results were obtained on a standard in-vitro test system.The activity is described in terms of the minimum inhibitoryconcentration (MIC) determined by the agar-dilution technique with aninoculum size of 10⁴ CFU/spot. Typically, compounds are active in therange 0.01 to 256 μg/ml.

Staphylococci were tested on agar, using an inoculum of 10⁴ CFU/spot andan incubation temperature of 37° C. for 24 hours—standard testconditions for the expression of methicillin resistance.

Streptococci and enterococci were tested on agar supplemented with 5%defibrinated horse blood, an inoculum of 10⁴ CFU/spot and an incubationtemperature of 37° C. in an atmosphere of 5% carbon dioxide for 48hours—blood is required for the growth of some of the test organisms.

MIC (μg/ml) Example Example Example Organism Example 4 12 18 151Staphylococcus aureus; Oxford 0.25 0.25 0.25 0.13 Novb. Res 0.50 0.50.25 0.25 MRQR 0.50 0.5 0.5 0.25 Coagulase Negative Staphylococci MS0.13 0.13 0.13 0.13 MR 0.50 0.5 0.5 0.25 Streptococcus pyogenes C2030.50 0.5 0.25 0.25 Enterococcus faecalis 1.00 1.00 0.5 0.25 Bacillussubtilis 0.25 0.25 0.25 0.13 Novb. Res = Novobiocin resistant MRQR =methicillin resistant quinolone resistant MR = methicillin resistant MS= methicillin sensitive

Certain Reference Examples described hereinafter (for example, ReferenceExamples 9, 10, 11, 30, 38 & 39) may also possess useful activity.

The invention is now illustrated but not limited by the followingExamples in which unless otherwise stated:

i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at ambient temperature, that istypically in the range 18-26° C. and in air unless otherwise stated, orunless the skilled person would otherwise work under an inertatmosphere;

(iii) column chromatography (by the flash procedure) was used to purifycompounds and was performed on Merck Kieselgel silica (Art. 9385) unlessotherwise stated;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the structure of the end-products of the formula (I) were generallyconfirmed by NMR and mass spectral techniques [proton magnetic resonancespectra were generally determined in DMSO-D6 unless otherwise statedusing a Varian Gemini 2000 spectrometer operating at a field strength of300 MHz, or a Bruker AM250 spectrometer operating at a field strength of250 MHz; chemical shifts are reported in parts per million downfieldfrom tetramethysilane as an internal standard (δ scale) and peakmultiplicities are shown thus: s, singlet; d, doublet; AB or dd, doubletof doublets; t, triplet, m, multiplet; fast-atom bombardment (FAB) massspectral data were generally obtained using a Platform spectrometer(supplied by Micromass) run in electrospray and, where appropriate,either positive ion data or negative ion data were collected];

(vi) intermediates were not generally fully characterised and purity wasin general assessed by thin layer chromatographic, infra-red (IR), massspectral (MS) or NMR analysis; and

(vii) in which the following abbreviations may be used:

® is a Trademark; DMF is N,N-dimethylformamide; DMA isN,N-dimethylacetamide; TLC is thin layer chromatography; HPLC is highpressure liquid chromatography; MPLC is medium pressure liquidchromatography; DMSO is dimethylsulfoxide; CDCl₃ is deuteratedchloroform; MS is mass spectroscopy; ESP is electrospray; THF istetrahydrofuran; TFA is trifluoroacetic acid; NMP isN-methylpyrrolidone; HOBT is 1-hydroxy-benzotriazole; EtOAc is ethylacetate; MeOH is methanol; phosphoryl is (HO)₂—P(O)—O—; phosphiryl is(HO)₂—P—O—; EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(hydrochloride); PTSA is para-toluenesulfonic acid.

EXAMPLE 15(R)-Isoxazol-3-yloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one

Diisopropylazodicarboxylate (248 mg, 1.22 mmol) was added dropwise, atambient temperature, to a stirred solution of5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one(International Patent Application Publication WO 97/09328) (300 mg, 1.02mmol), 3-hydroxyisoxazole (104 mg, 1.22 mmol) and triphenylphosphine(340 mg, 1.30 mmol) in THF (8.0 ml). The resulting solution was stirredat ambient temperature for 30 minutes before evaporating the solvent togive an oil which was purified by flash chromatography (Merck 9385silica, EtOAc/iso-hexane (7:3) eluant) to give the title product (219mg, 59%) as a crystalline solid.

¹H-NMR (300 MHz, CDCl₃): δ=2.45-2.55 (m, 2H), 3.88-4.00 (m, 3H), 4.17(t, 1H), 4.33 (m, 2H), 4.50 (dd, 1H), 4.58 (dd, 1H), 5.04 (m, 1H), 6.01(d, 1H), 6.06 (m, 1H), 7.22-7.32 (m, 2H), 7.42 (d, 1H), 8.15 (d, 1H).MS: ESP⁺ (M+H)⁺=361.

EXAMPLE 25(R)-(5-Methylisoxazol-3-yloxymethyl)-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one

5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one(300 mg, 1.02 mmol), 3-hydroxy-5-methylisoxazole (120 mg, 1.21 mmol),triphenylphosphine (270 mg, 1.03 mmol) and diisopropylazodicarboxylate(204 mg, 1.01 mmol) were reacted in THF (8.0 ml) using the generalmethod of Example 1. The resultant product was purified by flashchromatography (Merck 9385 silica, EtOAc/isohexane (7:3) eluant) to givethe title product (176 mg, 46%) as a crystalline solid.

¹H-NMR (300 MHz, CDCl₃): δ=2.34 (s, 3H), 2.45-2.55 (m, 2H), 3.86-4.00(m, 3H), 4.14 (t, 1H), 4.32 (m, 2H), 4.46 (dd, 1H), 4.54 (dd, 1H), 5.02(m, 1H), 5.65 (s, 1H), 6.05 (m, 1H), 7.20-7.32 (m, 2H), 7.42 (d, 1H).MS: ESP⁺ (M+H)⁺=375.

REFERENCE EXAMPLE 13,5-Difluoro-4-(1-benzyl-4-hydroxyhexahydropyrid-4-yl)aniline

nBuLi (1.32M in hexanes, 350 ml, 0.462 mol) was added dropwise over 20minutes to a solution ofN,N-(1,2-bis(dimethylsilyl)ethane)-3,5-difluoroaniline, (108.4 g, 0.40mol, J. Org. Chem., 60, 5255-5261 (1995)) in 800 ml dry THF at −70° C.under argon. After stirring for a further 4 hours at −70° C.,N-benzyl-4-piperidone (87.8 g, 0.46 mol) in 270 ml dry THF was addeddropwise over 40 minutes at the same temperature and the reactionallowed to stir to ambient temperature overnight. Solvent was removed invacuo and the resultant product treated with ice and conc.HCl andextracted with ether. The aqueous acidic phase was then treated with 40%NaOH with cooling, extracted with ether (and worked up by washing withwater, with brine and drying with an anhydrous drying agent such asmagnesium sulfate or sodium sulfate before evaporation—this work upprocedure is referred to as work up in the usual manner hereinafter) togive 144.7 g of a sludge. Analysis by TLC using 10% MeOH/dichloromethaneon silica indicated that the desired alcohol was present asapproximately 90% of the product, and the crude product was used withoutfurther purification. MS: ESP+ (M+H)=319.

REFERENCE EXAMPLE 23,5-Difluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)aniline

The crude product from Reference Example 1 (144.7 g) was suspended in400 ml conc.HCl and heated at reflux with stirring for 18 hours. TLCshowed all starting material had reacted and after cooling in ice thereaction mixture was taken to pH 11 with conc. NH₃ (aq) and extractedthree times with dichloromethane. Usual work-up gave 119.5 g of aviscous oil. TLC indicated a purity of ca. 80% and the crude product wasused without further purification. MS: ESP+ (M+H)=301.

REFERENCE EXAMPLE 3N-Benzyloxycarbonyl-3,5-difluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)aniline

The crude aniline from Reference Example 2 (3.2 g, 10.7 mmol ) in 10 mlof acetone was added in one portion to a stirred solution of sodiumdihydrogen phosphate (3.0 g) in 30 ml water. The resulting mixture wascooled to 5-10° C. and a solution of benzylchloroformate (2.18 g, 1.8ml, 12.8 mmol ) in 10 ml of acetone was added dropwise. The mixture wasstirred for a further hour at ice-bath temperature and then at ambienttemperature for 2 hours. The mixture was diluted with 80 ml water,basified with conc.NH₃(aq) and extracted with EtOAc. Usual work-up gavea viscous oil which was purified by flash chromatography (Merck 9385silica, EtOAc/isohexane (3:7 eluant) and triturated with isohexane togive a solid (1.53 g 33%). MS: ESP+ (M+H)=434.

REFERENCE EXAMPLE 45(R)-Hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

The benzylurethane from Reference Example 3 (5.54 g, 12.76 mmol ) in 50ml dry THF was cooled to −70° C. under nitrogen and 8.80 ml of 1.6MnBuLi in hexanes (14.08 mmol ) added dropwise at the same temperature.After 20 minutes at the same temperature a solution of (R)-glycidylbutyrate (2.00 g, 13.88 mmol in 5 ml THF) was added dropwise and themixture stirred for 30 minutes at −70° C., and then stirred to ambienttemperature overnight. After quenching with 100 ml 10% ammoniumchloride, the mixture was extracted with EtOAc and usual work-up to givean oily solid, which was purified by flash chromatography (Merck C60silica, 5% MeOH/dichloromethane eluant) to give a crystalline solid(4.40 g, 86%). MS: ESP+ (M+H)=401.

¹H-NMR (250 MHz, DMSO-d6): δ=2.32 (m, 2H), 2.63 (t, 2H), 3.05 (m, 2H),3.50-3.72 (m, 4H), 3.82 (dd, 1H), 4.06 (t, 1H), 4.73 (m, 1H), 5.18 (t,1H), 5.78 (m, 1H).

REFERENCE EXAMPLE 55(R)-Isoxazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 4 (2.6 g, 6.5 mmol ), 3-hydroxyisoxazole (0.60 g, 7.06mmol ), triphenylphosphine (1.96 g, 7.48 mmol ) anddiisopropylazodicarboxylate (1.44 g, 7.13 mmol ) in THF (40 ml) werereacted using the general method of Example 1. The resultant product waspurified by flash chromatograpy (Merck 9385 silica, EtOAc/isohexane(3:2) eluant initially, then repeated using methyl tert-butylethereluant) to give the title product (2.6 g, 86%) as a gum, MS: ESP⁺(M+H)⁺=468.

REFERENCE EXAMPLE 65(R)-Isoxazol-3-yloxymethyl-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 5 (2.6 g, 5.57 mmol ) in dichloromethane (40 ml) wascooled, under an atmosphere of nitrogen, in an ice-water bath then1-chloroethyl chloroformate (0.80 g, 5.59 mmol ) added dropwise viasyringe. The resulting solution was stirred at ice temperature for 1hour before isolating the intermediate product (carbamate) by flashchromatograhy (Merck 9385 silica, EtOAc/isohexane (1:1) eluant). Theresulting gum was taken up in MeOH (40 ml) and refluxed for 1 hour.Evaporation of the solvent after this time gave the title product (1.46g, 64%) as a crystalline solid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.54 (m, 2H), 3.27 (m, 2H), 3.72 (m, 2H),3.92 (dd, 1H), 4.20 (t, 1H), 4.38-4.52 (m, 2H), 5.10 (m, 1H), 5.88 (m,1H), 6.38 (d, 1H), 7.37 (m, 2H), 8.68 (d, 1H), 9.39 (s(broad), 2H). MS:ESP⁺ (M+H)⁺=378.

EXAMPLE 35(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R,S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (160 mg,0.84 mmol ) was added portionwise at ambient temperature to a stirredmixture of Reference Example 6 (300 mg, 0.72 mmol ),(R/S)-2,3-O-isopropylideneglyceric acid (122 mg, 0.84 mmol ) andtriethylamine (73 mg, 0.72 mmol ) in dichloromethane (6 ml). Theresulting mixture was stirred for 3 hours then left to stand overnightbefore washing with water. The dichloromethane solution was purified byflash chromatography (Merck 9385 silica. EtOAc/isohexane (3:1) eluant)to give the title product (143 mg, 39%) as a crystalline solid. MS: ESP⁺(M+H)⁺=506.

¹H-NMR (300 MHz, CDCl₃): δ=1.41 (s, 6H), 2.35-2.65 (m, 2H), 3.65-3.80(m, 1H), 3.92-4.00 (m, 2H), 4.10-4.22 (m, 3H), 4.22-4.45 (m, 1H),4.45-4.62 (m, 3H), 4.75 (t, 1H), 5.05 (m, 1H), 5.80-5.91 (m, 1H), 6.01(d, 1H), 7.18 (m, 2H), 8.16 (d, 1H).

EXAMPLE 45(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one

Example 3 (194 mg, 0.38 mmol ) in a mixture of THF (3 ml) and 1Nhydrochloric acid (1 ml) was left to stand at ambient temperature for 4days. The solvent was then evaporated to give an oil which was purifiedby flash chromatography (Merck 9385 silica, 10% MeOH/dichloromethaneeluant) to give the title product (144 mg, 80%) as a crystalline solid.MS: ESP⁺ (M+H)⁺=466.

¹H-NMR (300 MHz, DMSO-d6): δ=2.20-2.46 (m, 2H), 3.40-3.63 (m, 2H),3.63-3.85 (m, 2H), 3.92 (dd, 1H), 4.10 (m, 1H), 4.18 (t, 1H), 4.26-4.52(m, 4H), 4.68 (m, 1H), 4.96 (m, 1H), 5.10 (m, 1H), 5.86 (m, 1H), 6.37(d, 1H), 7.34 (m, 2H), 8.68 (d, 2H).

EXAMPLE 55(R)-Isoxazol-3-yloxymethyl-3-(4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 6 (300 mg, 0.72 mmol ) and triethylamine (102 mg, 1.01mmol ) in ethyl formate (10 ml) were refluxed for 12 hours, and thenevaporated to give an oil which was purified by flash chromatoraphy(Merck 9385 silica, 4% MeOH/dichloromethane eluant) to give the titleproduct (261 mg, 89%) as a crystalline solid.

¹H-NMR (300 MHz, CDCl₃): δ=2.18 & 2.37 (2s, 2H), 3.20-3.40 (m (partiallyobscured), 2H), 3.57-3.66 (m, 2H), 3.92 (m, 1H), 4.05 & 4.10 (2m, 2H),4.20 (t, 1H), 4.38-4.54 (m, 2H), 5.10 (m, 1H), 5.86 & 5.90 (2m, 1H),6.37 (d, 1H), 7.32 (m, 2H), 8.10 & 8.18 (2s, 1H), 8.68 (d, 1H). MS: ESP⁺(M+H)⁺=406.

EXAMPLE 65(R)-Isoxazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 6 (400 mg, 0.97 mmol ), triethylamine (205 mg, 2.03mmol ) and 4-(dimethylamino)pyridine (30 mg) in dichloromethane (10 ml)were cooled in an ice-water bath then acetoxyacetyl chloride (145 mg,1.06 mmol ) was added dropwise via syringe. The mixture was stirred atice temperature for 2 hours then purified by flash chromatography (Merck9385 silica, 2.5% MeOH/dichloromethane eluant) to give the title product(430 mg, 93%) as a crystalline solid.

¹H-NMR (300 MHz, CDCl₃): δ=2.20 (s, 3H), 2.40-2.56 (m, 2H), 3.59 (t,1H), 3.82 (t, 1H), 3.95 (dd, 1H), 4.08 & 4.25 (2m 2H), 4.12 (t, 1H),4.50 (dd, 1H), 4.58 (dd, 1H), 4.74 & 4.78 (2s, 2H), 5.05 (m, 1H), 5.80 &5.88 (2m, 1H), 6.00 (d, 1H), 7.19 (m, 2H), 8.17 (d, 1H). MS: ESP⁺(M+H)⁺=478.

EXAMPLE 75(R)-Isoxazol-3-yloxymethyl-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Example 6 (280 mg, 0.59 mmol ) and potassium carbonate (150 mg, 1.09mmol ) in MeOH (6 ml) were stirred at ambient temperature for 4 hours.Water (30 ml) was added to give a crystalline solid, which was filtered,washed with water and dried to give the title product (215 mg, 84%). MS:ESP⁺ (M+H)⁺=436.

¹H-NMR (300 MHz, DMSO d-6): δ=2.22-2.42 (m, 2H), 3.52 (m, 1H), 3.68 (m,1H), 3.92 (dd, 1H), 4.00-4.24 (m, 5H), 4.40-4.52 (m, 2H), 4.52-4.76 (m,1H), 5.10 (m, 1H), 5.86 (m, 1H), 6.36 (d, 1H), 7.35 (m, 2H), 8.68 (d,2H).

REFERENCE EXAMPLE 75(R)-Hydroxymethyl-3-(4-(4-(5-cyanopyrid-2-yl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one

5(R)-hydroxymethyl-3-(3-fluoro-4-(4-t-butoxycarbonylpiperazin-1-yl)phenyl)oxazolidin-2-one(International Patent Application Publication WO 93/23384. 43.1 g, 0.11M) was suspended by stirring in ethanol (1000 ml) under nitrogen. Anethanol solution of hydrogen chloride (3.8 M, 400 ml) was added slowly,and the mixture was stirred at ambient temperature for 18 hours. Theresulting precipitate was filtered, washed with diethyl ether (3×250ml), and dried, to give5(R)-hydroxymethyl-3-(3-fluoro-4-(piperazin-1-yl)phenyl)oxazolidin-2-onehydrochloride. A further crop was obtained by evaporation of the motherliquors to give a total yield of 38.7 g.

¹H-NMR (300 MHz, DMSO-D6) δ: 3.17 (m, 8H); 3.53 (dd, 1H); 3.64 (dd, 1H);3.79 (dd, 1H) 4.03 (t, 1H); 4.66 (m, 1H); 7.10 (t, 1H); 7.21 (dd, 1H);7.52 (dd, 1H) 9.39 (br s, 2H). MS: ESP+ (M+H)⁺=296.

5(R)-hydroxymethyl-3-(3-fluoro-4-(piperazin-1-yl)phenyl)oxazolidin-2-onehydrochloride (25 g, 75.4 mmol ) was suspended by stirring inacetonitrile (700 ml) under nitrogen, and triethylamine (16.8 g, 166mmol ) added, The mixture was stirred for 10 minutes and then2-chloro-5-cyanopyridine (10.3 g, 75.4 mmol ) added, and the mixtureheated under reflux for 18 hours. After cooling, the resultant solid wasfiltered, washed with water (3×500 ml) and diethyl ether (2×500 ml) togive5(R)-hydroxymethyl-3-(4-(4-(5-cyanopyrid-2-yl)piperazin-1-yl)-3-fluorophenyl)-oxazolidin-2-one.A further crop was obtained by evaporation of the mother liquors to givea total yield of 23.2 g. MS: ESP+ (M+H)⁺=398.

¹H-NMR (300 MHz, DMSO-D6)δ: 3.03 (t, 4H); 3.54 (m, 1H); 3.63(m, 1H);3.78 (t overlapping m, 5H); 4.03 (t, 1H); 4.66 (m, 1H); 5.18 (t, 1H);6.97 (d, 1H); 7.07 (t, 1H); 7.20 (dd, 1H); 7.53 (dd, 1H); 7.85 (dd, 1H);8.49 (d, 1H).

EXAMPLE 85(R)-Isoxazol-3-yloxymethyl-3-(4-(4-(5-cyanopyrid-2-yl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one

Reference Example 7 (397 mg, 1 mmol ), 3-hydroxyisoxazole (85 mg, 1.1mmol ) and polymer bound triphenylphosphine (3 mmol /g, 416 mg, 1.25mmol ) were suspended with stirring in 10 ml dry THF anddiisopropylazodicarboxylate (242 mg, 1.2 mmol) added dropwise bysyringe, and the mixture stirred at ambient temperature for 1 hour. Themixture was filtered, evaporated to dryness, and dissolved in EtOAc andpurified by chromatography (on a 10 g silica Mega Bond Elut® column,eluting with a gradient increasing in polarity from 80 to 100% EtOAc inisohexane) to give the title product (93 mg). MS: ESP+: (M+H)⁺=465.

¹H-NMR (300 MHz, DMSO-D6) δ: 3.06 (t, 4H); 3.80 (t, 4H); 3.87 (dd, 1H);4.16 (t, 1H); 4.42 (dd, 1H); 4.48 (dd, 1H); 5.04 (m, 1H); 6.37 (d, 1H);6.97 (d, 1H); 7.08 (t, 1H); 7.20 (dd, 1H); 7.51 (dd, 1H); 7.86 (dd, 1H);8.49 (d, 1H); 8.67 (d, 1H).

EXAMPLE 95(R)-Isothiazol-3-yloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-Pyran-4-yl)phenyl)oxazolidin-2-one

Diisopropylazodicarboxylate (227 mg, 1.12 mmol) was added dropwise, atambient temperature, to a stirred solution of5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one(300 mg, 1.02 mmol ; see Example 1), 3-hydroxyisothiazole (114 mg, 1.13mmol) and triphenylphosphine (304 mg, 1.16 mmol) in THF (8.0 ml). Theresulting solution was stirred at room temperature for 30 minutes beforeevaporating the solvent to give an orange oil. It was purified by flashchromatography (Merck 9385 silica, EtOAc/isohexane (3:2)) to give thetitle product (257 mg, 67%) as a colourless crystalline solid. MS: ESP⁺(M+H)⁺=377.

¹H-NMR (300 MHz, CDCl₃): δ=2.45-2.55 (m, 2H), 3.94 (t, 2H), 3.98 (dd,1H), 4.14 (t, 1H), 4.32 (m, 2H), 4.61-4.72 (m, 2H), 5.04 (m, 1H), 6.07(m, 1H), 6.62 (d, 1h), 7.22-7.30 (m, 2H), 7.42 (dd, 1H), 8.48 (d, 1H).

EXAMPLE 105(B)-(1,2,5-Thiadiazol-3-yloxymethyl)-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one

A solution of5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one(0.275 g, 0.93 mmol ; see Example 1), 3-hydroxy-1,2,5-thiadiazole(Weinstock et al, J.Org. Chem, 32, 2823 (1967)) (0.112 g, 1.1 mmol), andtriphenylphosphine (0.288 g, 1.1 mmol) was stirred in dry THF (7 ml) atambient temperature and diisopropylazodicarboxylate (0.22 g. 1.1 mmol)in dry THF (1.0 ml) added dropwise over ten minutes. After 1.5 hours,tlc (70% EtOAc/isohexane) showed essentially complete reaction. Thereaction mixture was evaporated in vacuo and purified by chromatography(Merck 9385 silica, 50% EtOAc/isohexane eluant) to give the titleproduct (256 mg, 73%) as a colourless solid mp, 46-8 C.

¹H-NMR (300 MHz, DMSO-d6): δ=2.40 (m, 1H), 3.78 (m, 3H), 3.96 (dd, 1H),4.20 (m, 3H), 4.64 (m, 2H), 5.10 (m, 1H), 6.08 (s, 1H), 7.35 (m, 2H),7.50 (d, 1H), 8.41 (s, 1H). MS: ESP⁺ (M+H)⁺=377.

REFERENCE EXAMPLE 85(R)-(1,2,5-Thiadiazol-3-yloxymethyl)-3-phenyloxazolidin-2-one

Diisopropylazodicarboxylate (4.45 g, 22 mmol) was added dropwise to astirred solution of 5(R)-hydroxymethyl-3-phenyloxazolidin-2-one (Gregoryet al. J. Med, Chem, 32, 1673 (1989); 4.25 g,22 mmol), triphenylphosphine (5.76 g, 22 mmol) and 3-hydroxy-1,2,5-thiadiazole (Weinstocket al, J.Org. Chem, 32, 2823 (1967)) (2.04 g, 20 mmol) in 30 ml THF, inan ice-bath. After stirring at ambient temperature for two hours andevaporating in vacuo, the resulting oil was purified by chromatography(Merck 9385 silica. Gradient elution from isohexane to ca. 50%EtOAc/isohexane to give a white solid. Further purification by flashchromatography on silica using 1% MeOH/dichloromethane was necessary toremove remaining diisopropylcarboxyhydrazine yielding the title productas a white crystalline solid (4.7 g, 83%). MS: ESP⁺ (M+H)⁺=278.

¹H-NMR (300 MHz,CDCl₃): δ=4.0 (dd, 1H), 4.21 (t, 1H), 4.6-4.77 (m, 2H),5.04 (m, 1H), 7.17 (t, 1H), 7.39 (m, 2H), 7.56 (d, 2H), 8.0 (s, 1H).

REFERENCE EXAMPLE 95(R)-(1,2,5-Thiadiazol-3-yloxymethyl)-3-(4-iodophenyl)oxazolidin-2-one

Silver trifluoroacetate (0.727 g, 3.29 mmol) was added to a stirredsolution of the compound of Reference Example 8 (0.70 g, 2.53 mmol) inchloroform/acetonitrile (6 ml/4 ml) at ambient temperature. Iodine (0.67g, 2.64 mmol) was then added in portions. The resulting brown mixturewas then stirred for 65 h with protection from light. A yellow solid wasfiltered off, washing with chloroform, The filtrate and washings wereevaporated in vacuo, the residue redissolved in EtOAc and washed withdilute ammonium hydroxide, water and brine. Dried over sodium sulfateand evaporated in vacuo to give a pale yellow solid on standing.Trituration with ether gave the title product as an off-white solid(0.749 g, 73%).

¹H-NMR (300 MHz, DMSO-d₆): δ=3.95 (dd, 1H), 4.19 (t, 1H), 4.67 (m, 2H),5.1 (m, 1H), 7.37 (d, 2H), 7.69 (d, 2H), 8.4 (s, 1H). MS: ESP+(M+H)⁺=404.

REFERENCE EXAMPLE 105(R)-Isoxazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 1 using as starting material5(R)-hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one(WO97/30995; 4.0 g, 10.5 mmol), 3-hydroxyisoxazole (1.0 g, 11.8 mmol),triphenylphosphine (3.24 g, 12.4 mmol) and diisopropylazodicarboxylate(2.36 g, 11.7 mmol) in tetrahydrofuran (60 ml). Purified by flashchromatography (Merck 9385 silica; tert-butyl methyl ether/EtOAc/MeOH(70:30:0.5) eluant) to give the product (3.0 g, 64%) as a colourlesscrystalline solid. MS: ESP³⁰ (M+H)⁺=450.

REFERENCE EXAMPLE 115(R)-Isoxazol-3-yloxymethyl-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Reference Example 6 using ReferenceExample 10 (7.09 g, 15.8 mmol) and 1-chloroethyl chloroformate (2.26 g,15.8 mmol) in dichloromethane (120 ml) to give the product (3.71 g, 59%)as a pale yellow crystalline solid. MS: ESP⁺ (M+H)⁺=360.

¹H-NMR (300 MHz, DMSO-d6): d=2.64 (m, 2H), 3.22-3.30 (m, 2H), 3.72 (m,2H), 3.92 (dd, 1H), 4.21 (t, 1H), 4.40-4.55 (m, 2H), 5.10 (m, 1H), 6.02(m, 1H), 6.38 (d, 1H), 7.32-7.44 (m, 2H), 7.52 (d, 1H), 8.68 (d, 1H),9.30 (s(br), 2H).

EXAMPLE 115(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

1,3 Dicyclohexylcarbodiimide (550 mg, 2.67 mmol) was added in one go atambient temperature to a stirred solution of(S)-2,3-O-isopropylidineglyceric acid (390 mg, 2.67 mmol) and1-hydroxybenzotriazole (410 mg, 2.58 mmol) in dichloromethane (10 ml).The resulting suspension was stirred for 1 hr then a further 10 mldichloromethane was added, followed by Reference Example 11 (1.0 g, 2.53mmol) and N,N-diisopropylethylamine (326 mg, 2.53 mmol). The reactionwas stirred at ambient temperature for 18 hr then filtered, The filtratewas washed with water (2X) and brine then purified by flashchromatography (Merck 9385 silica; 2% MeOH in dichloromethane eluant) togive the product (754 mg, 61%) as a colourless crystalline solid. MS:ESP⁺ (M+H)⁺=488.

¹H-NMR (300 MHz, CDCl₃): d=1.44 (s, 6H), 2.45-2.72 (m, 2H), 3.62-3.76(m, 1H), 3.89-4.05 (m, 2H), 4.10-4.20 (m, 3H), 4.24-4.38 (m, 1H),4.44-4.62 (m, 3H), 4.75 (m, 1H), 5.04 (m, 1H), 5.97 (m, 1H), 6.00 (d,1H), 7.25 (m, 2H), 7.45 (d, 1H), 8.15 d, 1H).

EXAMPLE 125(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 4 using Example 11 (754 mg,1.55 mmol) in a mixture of THF (15 ml) and 1N hydrochloric acid (5 ml).Purified by flash chromatography (Merck 9385 silica; 10% MeOH indichloromethane eluant) to give the product (486 mg, 70%) as acolourless crystalline solid, mp 140-143° C.

¹H-NMR (300 MHz, DMSO-d6): d=2.42 (m, 2H), 3.40-3.60 (m, 2H), 3.62-3.85(m, 2H), 3.92 (dd 1H), 4.10-4.30 (m, 3H), 4.30-4.56 (m, 3H), 4.79 (m,1H), 4.94 (m, 1H), 5.09 (m, 1H), 6.00 (m, 1H), 6.37 (d, 1H), 7.28-7.44(m, 2H), 7.50 (d, 1H), 8.66 (d, 1H). MS: ESP⁺ (M+H)⁺=448. HPLC:Chiralpak AD (250 mm×4.6 mm i.d,), 100% MeOH eluant, 1 ml/min. flowrate: ret. time=42.5 min.

EXAMPLE 135(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 11 using(R)-2,3-O-isopropylidineglyceric acid (390 mg, 2.67 mmol),1-hydroxybenzotriazole (410 mg, 2.58 mmol), dicyclohexylcarbodiimide(550 mg, 2.67 mmol), Reference Example 11 (1.0 g, 2.53 mmol) andN,N-diisopropylethylamine (326 mg, 2.53 mmol) in dichloromethane (20ml). Purified by flash chromatography (Merck 9385 silica; 2% MeOH indichloromethane eluant) to give the product (682 mg, 55%) as acolourless crystalline solid. MS: ESP⁺ (M+H)⁺=488.

¹H-NMR (300 MHz, CDCl₃): d=1.44 (s, 6H), 2.45-2.72 (m, 2H), 3.62-3.76(m, 1H), 3.89-4.05 (m, 2H), 4.10-4.20 (m, 3H), 4.24-4.38 (m, 1H),4.44-4.62 (m, 3H), 4.75 (m, 1H), 5.04 (m, 1H), 5.97 (m, 1H), 6.00 (d,1H), 7.25 (m, 2H), 7.45 (d, 1H), 8.15 d, 1H).

EXAMPLE 145(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 12 using Example 13 (682 mg,1.40 mmol) in a mixture of THF (15 ml) and 1N hydrochloric acid (5 ml).Purified by flash chromatography (Merck 9385 silica; 10% MeOH indichloromethane eluant) to give the product (466 mg, 74%) as acolourless crystalline solid: mp 136-140° C.

¹H-NMR (300 MHz, DMSO-d6): d=2.42 (m, 2H), 3.40-3.60 (m, 2H), 3.62-3.85(m, 2H), 3.92 (dd, 1H), 4.10-4.30 (m, 3H), 4.30-4.56 (m, 3H), 4.79 (m,1H), 4.94 (m, 1H), 5.09 (m, 1H), 6.00 (m, 1H), 6.37 (d, 1H), 7.28-7.44(m, 2H), 7.50 (d, 1H), 8.66 (d, 1H). MS: ESP⁺ (M+H)⁺=448. HPLC:Chiralpak AD (250 mm×4.6 mm i.d,), 100% MeOH eluant. 1 ml/min. flowrate: ret. time=18.5 min.

EXAMPLE 155(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

1,3 Dicyclohexylcarbodiimide (315 mg, 1.53 mmol) was added in one go atambient temperature to a stirred mixture of Reference Example 6 (660 mg,1.45 mmol), (R)-2,3-O-isopropylidineglyceric acid (240 mg, 1.64 mmol)and pyridine (115 mg, 1.45 mmol) in dichloromethane (15 ml). Theresulting mixture was stirred at ambient temperature for 18 hr thenpurified by flash chromatography (Merck 9385 silica; EtOAc/isohexane(3:1) eluant) to give the product (315 mg, 43%) as a colourlesscrystalline solid.

EXAMPLE 165(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 14 using Example 15 (315 mg,0.62 mmol) in a mixture of THF (6 ml) and 1N hydrochloric acid (2 ml).Purified by flash chromatography (Merck 9385 silica; 10% MeOH indichloromethane eluant) to give the product (208 mg, 72%) as acolourless crystalline solid: mp 128-134 ° C.

¹NMR (300 MHz, DMSO-d₆): d 2.20-2.46 (m, 2H), 3.40-3.63 (m, 2H),3.63-3.85 (m, 2H), 3.92 (dd, 1H), 4.10 (m, 1H), 4.18 (t, 1H), 4.26-4.52(m, 1H), 4.68 (m, 1H), 4.96 (m, 1H), 5.10 (m, 1H), 5.86 (m, 1H), 6.37(d, 1H), 7.34 (m, 2H), 8.68 (d, 2H). MS: ESP⁺ (M+H)⁺=466. HPLC:Chiralpak AD (250 mm×4.6 mm i.d,), 100% MeOH eluant. 1 ml/min. flowrate: ret. time=11.2 min.

EXAMPLE 175(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 15 using 1,3dicyclohexylcarbodiimide (315 mg, 1.53 mmol). Reference Example 6 (660mg, 1.45 mmol), (S)-2,3-O-isopropylidineglyceric acid (240 mg, 1.64mmol) and pyridine (115 mg, 1.45 mmol) in dichloromethane (15 ml).Purified by flash chromatography (Merck 9385 silica; EtOAc/isohexane(3:1) eluant) to give the product (282 mg, 38%) as a colourlesscrystalline solid. MS: ESP⁺ (M+H)⁺=506.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (s, 3H), 1.34 (s, 3H), 2.25-2.50 (m,2H), 3.63-3.87 (m, 2H), 3.95 (dd, 1H), 4.02-4.32 (m, 4H), 4.43-4.55 (m,2H), 4.92 (m, 1H), 5.12 (m, 1H), 5.89 (m, 1H), 6.37 (d, 1H), 7.35 (d,2H), 8.68 (d, 1H).

EXAMPLE 185(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 16 using Example 17 (282 mg,0.56 mmol) in a mixture of THF (6 ml) and 1N hydrochloric acid (2 ml).Purified by flash chromatography (Merck 9385 silica; 10% MeOH indichloromethane eluant) to give the product (183 mg, 70%) as acolourless crystalline solid: mp 136-142° C.

¹NMR (300 MHz, DMSO-d₆): d 2.20-2.46 (m, 2H), 3.40-3.63 (m, 2H),3.63-3.85 (m, 2H), 3.92 (dd, 1H), 4.10 (m, 1H), 4.18 (t, 1H), 4.26-4.52(m, 1H), 4.68 (m, 1H), 4.96 (m, 1H), 5.10 (m, 1H), (m, 1H), 6.37 (d,1H), 7.34 (m, 2H) 8.68 (d, 2H). MS: ESP⁺ (M+H)⁺=466. HPLC: Chiralpak AD(250 mm×4.6 mm i.d,), 100% MeOH eluant, 1 ml/min. flow rate: ret.time=38.4 min.

REFERENCE EXAMPLE 125(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-di-(di-t-butoxyphosphoryl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Di-tert-butyl N,N diethylphosphoramidite (1.67 g, 6.24 mmol) was addeddropwise at room temperature, under an atmosphere of nitrogen, to astirred suspension of Example 12 (1.0 g, 2.24 mmol) and 1H-tetrazole(1.4 g, 20.0 mmol) in tetrahydrofuran (40 ml). The resulting mixture wasstirred for 2 hr, then cooled to −40° C. and treated portionwise with3-chloroperoxybenzoic acid (1.9 g 60% strength, 6.6 mmol). The reactionwas stirred at −40 to −20° C. for 1 hr, then diluted with EtOAc (150ml), washed succesively with 10% aqueous sodium bisulfite solution, sat.sodium bicarbonate solution and water, dried over magnesium sulfate andevaporated to give a colourless oil.Purified by flash chromatography(Merck 9385 silica, 20-30% acetonitrile/EtOAc) to give the product (625mg, 34%) as a colourless foam.

¹H-NMR (300 MHz, CDCl₃): δ=1.48 (m, 36H), 2.45-2.70 (m, 2H), 3.58-3.71 &3.73-3.86 (m, 1H), 3.92-4.10 (m, 2H), 4.10-4.38 (m, 5H), 4.47-4.62 (m,2H), 4.97-5.08 (m, 1H), 5.22-5.32 (m, 1H), 5.88 (m, 1H), 6.02 (d, 1H),7.18-7.28 (m, 2H), 7.43 (d, 1H), 8.16 (d, 1H). MS: ESP⁺ (M+H)⁺=832.

EXAMPLE 195(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

A 4M solution of HCl in dioxane (6 ml) was added in one go at roomtemperature to a stirred solution of Reference Example 12 (600 mg, 0.72mmol) in dioxane (6 ml). The resulting yellow mixture was stirred 1 hr,then concentrated under reduced pressure. Trituration with diethyl ethergave a yellow solid which was filtered, washed with ether, dried andthen dissolved in water and lyophilized to a pale yellow solid (435 mg).

¹H-NMR (300 MHz, DMSO-d6+CD₃COOD): δ=2.35-2.50 (m, 2H), 3.52-3.68 &3.70-3.85 (m, 2H), 3.90 (dd, 1H), 4.05-4.35 (m, 5H), 4.35-4.53 (m, 2H),5.05 (m, 1H), 5.10-5.25 (m, 1H), 5.98 (m, 1H), 6.25 (d, 1H), 7.25-7.40(m, 2H), 7.45 (dd, 1H), 8.54 (d, 1H). MS: ESP⁺ (M+H)⁺=608.

REFERENCE EXAMPLE 135(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(di-t-butoxyphosphoryl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2one

To a stirred solution of the starting material Example 12 (600 mg, 1.34mmol) and 1H-tetrazole (310 mg, 4.43 mmol) in THF (30 ml) under nitrogenwas added di-tert-butyl N,N diethylphosphoramidite (368 mg, 1.48 mmol)over a few minutes. After stirring for 90 minutes the solution wascooled to −40° C. and 3-chloroperoxybenzoic acid (425 mg 60% strength,1.48 mmol) added in portions. The reaction mixture was allowed to warmto ambient temperature and stirred for 30 minutes. EtOAc was added, thesolution washed with sodium metabisulfite, sodium bicarbonate and brinesolutions, the organic phase dried over anhydrous magnesium sulfate andevaporated in vacuo. The crude product was purified by flashchromatography (Merck 9385 silica, 10-20% acetonitrile/EtOAc) to givethe title compound (165 mg, 19%) as a colourless gum.

¹H-NMR (300 MHz, CDCl₃): δ=1.48 (s, 9H), 1,50 (s, 9H), 2.45-2.80 (m,2H), 3.61-3.86 (m, 2H), 3.96 (dd, 1H), 4.02-4.12 (m, 3H), 4.16 (t, 1H),4.22-4.30 (m, 2H), 4.47-4.61 (m, 2H), 4.64-4.77 (m, 1H), 5.03 (m, 1H),6.00 (m, 1H), 6.03 (d, 1H), 7.20-7.30 (m, 2H), 7.46 (d, 1H), 8.16 (d,1H). MS: ESP⁺ (M+H)⁺=640.

EXAMPLE 205(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

TFA (2 ml) was added dropwise at room temperature to a stirred solutionof Reference Example 13 (165 mg, 0.26 mmol) in dichloromethane (8 ml).The resulting yellow solution was stirred 30 min. then evaporated underreduced pressure to a yellow foam, Trituration with diethyl ether gavethe title compound (120 mg) as a yellow solid.

¹H-NMR (300 MHz, DMSOd6+CD₃COOD): δ=2.30-2.50 (m, 2H), 3.50-3.65 &3.65-3.82 (m, 2H), 3.92 (dd, 1H), 3.97-4.40 (m, 5H), 4.40-4.62 (m, 3H),5.05 (m, 1H), 6.00 (m, 1H), 6.28 (d, 1H), 7.25-7.43 (m, 2H), 7.48 (d,1H), 7.57 (d, 1H). MS: ESP⁺ (M+H)⁺=528.

REFERENCE EXAMPLE 145(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-di-(di-t-butylphosphoryl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

The title compound was prepared, with only non-critical variations, bythe method for Reference Example 12 on a 4.3 mM scale, using as startingmaterial Example 18.

Yield=1.86 g (51%). NMR (300 Mz, DMSO-d6): δ 1.42 (s, 36H), 2.5 (m,partially obscured), 3.3-3.9 (m, 4H), 3.94 (d of d, 1H), 4.1 (s, 2H)4.21 (t, 1H), 4.48 (m, 2H), 5.14 (m, 2H), 5.90 (s, 1H), 6.38 (s, 1H),7.37 (d, 2H), 8.70 (s, 1H). MS: ESP+ (M+H)=850.

EXAMPLE 215(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

The title compound was prepared, with only non-critical variations, bythe method for Example 19 on a 1.4 mM scale, using as starting materialReference Example 14.

Yield=735 mg (98%). NMR (300 Mz, DMSO-d6): δ=2.5 (m, partiallyobscured), 3.57 & 3.77 (2m, 2H), 3.91 (d of d, 1H), 4.0-4.4 (m, 4H),4.18 (t, 1H), 4.58 (m, 2H), 5.1 (m, 2H), 5.85 (s, 1H), 6.36 (s, 1H),7.35 (d, 2H), 8.78 (s, 1H). MS: ESP+ (M+H)=626.

REFERENCE EXAMPLE 155(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(di-t-butylphosphoryl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of the starting material Example 18 (1.02 g, 2.2mmol) and tetrazole (462 mg, 6.6 mg) in THF (30 ml) at ambienttemperature under nitrogen, was added di-tert-butyl N,Ndiethylphosphoramidite (575 mg, 2.31 mmol) over ˜2 minutes. Afterstirring for 90 minutes the solution was cooled to −40° C. andm-chloroperbenzoic acid (2.5 mmol , 480 mg of 90% strength) was added inportions. The reaction mixture was allowed to warm to ambienttemperature and stir for 30 minutes. EtOAc was added and the mixture waswashed with aqueous sodium metabisulfite, saturated sodium bicarbonateand brine solutions. The organic phase was dried over anhydrous MgSO₄and evaporated under reduced pressure. The title compound was isolatedby MPLC (EtOAc) as a brittle glass (406 mg, 28%). MS: ESP+ (M+H)=658;ESP− (M−H)=656.

NMR (300 Mz, DMSO-d6): δ 1.42 (s, 18H), 2.5 (m, partially obscured),3.55-3.95 (m, 4H), 3.95 (d of d, 1H), 4.0-4.15 (m, 2H), 4.25 (t, 1H),4.50 (m, 2H), 4.63 (m, 1H), 5.14 (m, 1H), 5.54 (d, 1H), 5.91 (s, 1H),6.40 (s, 1H), 7.37 (d, 2H), 8.70 (1H, s).

EXAMPLE 225(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of the starting material Reference Example 15 (100mg, 0.15 mmol) in dioxan (1 ml) was added 4M HCl/dioxan (3 ml). Thesolution was stirred at ambient temperature for 30 mins. and thenevaporated. The residue was triturated well with ether giving the titlecompound as a white powder (80 mg, 96%).

NMR (300 Mz, DMSO-d6): 2.43 (m, partially obscured), 3.6-4.35 (m, 8H),4.35-4.60 (m, 3H), 5.09 (m, 1H), 5.85 (s, 1H), 6.30 (s, 1H), 7.31 (d,2H), 8.60 (s, 1H). MS: ESP+ (M+H)=546.

EXAMPLE 235(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(cyclo-2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred partial solution of the starting material Example 21 (100mg, 0.16 mmol) in THF (8 ml) was added dicyclohexyl carbodiimide (40 mg,0.195 mmol). DMF(4 ml) was added to give a clear solution. Afterstirring for 18 hrs at ambient temperature, more DCCI (40 mg, 0.195mmol) was added, The reaction was essentially complete by HPLC (PartisilSAX 10 μ column, 0.0M to 0.3M pH6.5 phosphate buffer gradient) after afurther 3 hrs. The solvent was evaporated and the residue was taken intowater and filtered, The filtrate was chromatographed by MPLC (0-25%acetonitrile/water gradient on Mitsubishi HP20SS polystyrene resin) andthe title compound was obtained by freeze drying after partialevaporation to remove acetonitrile.

Yield=49 mg (50%). MS: ESP− (M−H)=606. NMR (300 Mz, DMSO-d6): δ=2.4 (m,partially obscured), 3.7-4.0 (m, 3H), 4.18 (m, 4H), 4.48 (m, 3H), 5.05(m, 1H), 5.19 & 5.30 (2 m, 1H), 5.85 (s, 1H), 6.30 (s, 1H), 7.31 (d,2H), 8.59 (s, 1H).

EXAMPLE 245(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(4-hydroxybutanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 6 (0.223 g, 0.54 mmol),4-hydroxybutyric acid sodium salt (0.082 g, 0.65 mmol) and HOBT (0.087g, 0.65 mmol) in DMF (5 ml) was added EDC (0.124 g, 0.65 mmol). Themixture was stirred for 4 days and then evaporated, The residue waspurified by MPLC [5% MeOH/CH₂Cl₂ as eluant] to give after triturationwith diethyl ether, as a white solid (0.141 g, 56%).

¹H-NMR (300 MHz, DMSO-d6): δ=1.63 (m, 2H), 2.29 (m, 1H), 2.38 (m, 2H),3.25 (d, 1H), 3.40 (m, 2H), 3.62 (m, 2H), 3.91 (dd, 1H), 4.10 (d, 1H),4.19 (t, 2H), 4.44 (m, 3H), 5.09 (m, 1H), 5.84 (s, 1H), 6.38 (d, 1H),7.36 (d, 2H) and 8.70 (d, 1H). MS: ESP⁻ (M+H)⁺=464.

EXAMPLE 255(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(4-methoxybutanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 6 (0.285 g, 0.69 mmol),2-(2-methoxyethoxy)acetic acid (0.111 g, 0.83 mmol), triethylamine(0.070 g, 0.096 ml, 0.69 mmol) and HOBT (0.112 g, 0.83 mmol) indichloromethane (5 ml) was added EDC (0.159 g, 0.83 mmol). The mixturewas stirred for 17 h and then the solution was washed with water (10ml), dried and evaporated, The residue was purified by MPLC [3% MeOH/CH₂_(Cl) ₂ as eluant] to give a colourless oil (0.201 g, 61%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.36 (d, 2H), 3.25 (s, 3H), 3.45 (m, 2H),3.59 (m, 4H), 3.92 (dd, 1H), 4.09 (m, 2H), 4.18 (m, 3H), 4.45 (m, 2H),5.09 (m, 1H), 5.86 (s, 1H), 6.38 (d, 1H), 7.35 (d, 2H) and 8.69 (d, 1H).

REFERENCE EXAMPLE 16 6-Hydroxymethyl-2-phenyl-1,3-dioxane

(D,L)-Malic acid (5.0 g, 37 mmol) in dry THF (25 ml) under nitrogen wastreated with trimethyl borate (12.5 ml) and borane-dimethylsulfide (2.0M in THF) (60 ml, 120 mmol) dropwise at 0° C. After the addition wascomplete stirring was continued at 0° C. for 5 min. During which time awhite precipitate formed. The ice-bath was removed and stirringcontinued overnight. After 17 h the solution was slowly treated withMeOH (30 ml) and then evaporated, The residue was purified by MPLC [10%MeOH/CH₂Cl₂ as eluant] to give the triol (3.57 g). This was dissolved inbenzaldehyde (150 ml) containing tosic acid (0.64 g, 3.37 mmol) andstirred for 60 h and then evaporated, The residue was dissolved indichloromethane, washed with saturated aqueous sodium hydrogencarbonate, dried and evaporated, The residue was was purified by MPLC[20→45% EtOAc/hexanes eluant] to give the product as an oil (1.47 g,22%). MS: ESP⁺ (M+H)⁺=195.

¹H-NMR (300 MHz, DMSO-d6): δ=1.50 (d, 1H), 1.62 (ddd, 1H), 3.38 (dd,1H), 3.48 (dd, 1H), 3.90 (m, 2H), 4.14 (dd, 1H), 4.70 (t, 1H), 5.49 (s,1H) and 7.38 (m, 5H).

REFERENCE EXAMPLE 17 6-Carboxy-2-phenyl-1,3-dioxane

To a stirred solution of the alcohol Reference Example 16 (1.47 g, 7.60mmol) in aqueous sodium hydroxide (7.60 mmol , 0.304 g in 30 ml) at 0°C. was added potassium permanganate (1.80 g, 11.4 mmol) portionwise.After 3.5 h the mixture was filtered and acidified to pH 2. The solutionwas saturated with sodium chloride and extracted with EtOAc (4×50 ml),dried and evaporated to a residue. This white solid was dissolved indichloromethane and extracted with ammonium hydroxide (2×15 ml). Thebasic extracts were acidified at 0° C. to pH 2 with conc. hydrochloricacid, and the acidic mixture extracted with dichloromethane (2×50 ml).The organics were dried and evaporated to give the acid as a gum (0.15g, 10%). MS: ESP⁺ (M+H)⁺=209.

¹H-NMR (300 MHz, DMSO-d6): δ=1.82 (m, 2H), 3.96 (m, 1H), 4.18 (dd, 1H),4.50 (dd, 1H), 5.58 (s, 1H), 7.40 (m, 5H) and 12.82 (s, 1H).

EXAMPLE 265(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-phenyl-1,3-dioxan-4(R,S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 6 (0.220 g, 0.53 mmol),Reference Example 17 (0.133 g, 0.64 mmol), triethylamine (0.054 g, 0.074ml, 0.53 mmol) and HOBT (0.086 g, 0.64 mmol) in dichloromethane (6 ml)was added EDC (0.123 g, 0.64 mmol). The mixture was stirred for 60 h andthen the solution was washed with 2N HCL (10 ml), brine (10 ml), driedand evaporated, The residue was purified by MPLC [4% MeOH/CH₂Cl₂ aseluant] to give an oil (0.246 g, 82%). MS: ESP⁺ (M+H)⁺=568.

¹H-NMR (300 MHz, DMSO-d6): δ=1.59 (d, 1H), 2.10 (m, 1H), 2.33 (m, 2H),3.55 (m, 1H), 3.78 (m, 1H), 3.90 (dd, 1H), 4.07 (m, 2H), 4.15 (m, 3H),4.45 (m, 2H), 4.90 (m, 1H), 5.10 (m, 1H), 5.71 (d, 1H), 5.88 (s, 1H),6.38 (d, 1H), 7.38 (m, 7H) and 8.70 (d, 1H).

REFERENCE EXAMPLE 185(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-t-butoxycarbonylamino-2(R,S)-hydroxy-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 6 (0.091 g, 0.22 mmol),(D,L)-N-BOC-isoserinc (0.054 g, 0.27 mmol), triethylamine (0.022 g,0.031 ml, 0.22 mmol) and HOBT (0.036 g, 0.27 mmol) in dichloromethane (3ml) was added EDC (0.052 g, 0.27 mmol). The mixture was stirred for 18 hand then the solution was washed with 2N HCL (10 ml), brine (10 ml),dried and evaporated. The residue was purified by MPLC [3% MeOH/CH₂Cl₂as eluant] to give the product as a tan solid (0.047 g, 38%). MS: ESP⁺(M+H)⁺=565.

EXAMPLE 275(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-amino-2(R,S)-hydroxy-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 18 (0.047 g, 0.083 mmol) was dissolved in EtOAc (3 ml)saturated with hydrogen chloride and stirred for 18 h. The solution wasevaporated and triturated with EtOAc to give the product as an off-whitesolid (0.034 g, 88%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.30 (d, 2H), 3.70 (m, 2H), 3.90 (dd, 1H),45.19 (m, 4H), 4.44 (m, 2H), 4.60 (m, 1H), 5.10 (m, 1H), 5.90 (s, 1H),6.37 (d, 1H), 7.30 (s, 1H), 7.38 (s, 1H), 7.89 (s, 3H) and 8.69 (d, 1H).MS: ESP⁺ (M+H)⁺=465.

EXAMPLE 285(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-phenyl-1,3-dioxan-5(R,S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 6 (0.344 g, 0.83 mmol),5-carboxy-2-phenyl-1,3-dioxan (JOC, 1997, 62, 4029) (0.208 g, 1.00mmol), triethylamine (0.084 g, 0.116 ml, 0.83 mmol) and HOBT (0.135 g,0.1.00 mmol) in dichloromethane (10 ml), was added EDC (0.192 g, 1.00mmol). The mixture was stirred for 24 h and then the solution was washedwith 2N HCL (10 ml), brine (10 ml), dried and evaporated. The residuewas purified by MPLC [2% MeOH/CH₂Cl₂ as eluant] to give the product asan oil (0.357 g, 76%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.38 (d, 2H), 2.99 (s, 1H), 3.70 (d, 2H),3.90-4.55 (m, 10H), 5.10 (m, 1H), 5.55 (s, 1H), 5.90(s, 1H), 6.37 (d,1H), 7.40 (m, 7H) and 8.68 (d, 1H). MS: ESP⁺ (M+H)⁺=568.

EXAMPLE 295(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-hydroxy-2-hydroxymethyl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Example 28 (0.155 g, 0.27 mmol) in dichloromethane (4 ml) at 0° C. wastreated with boron trichloride-dimethyl sulfide (2.0 M in CH₂Cl₂) (0.40ml, 0.81 mmol) for 4.5 h. MeOH (1 ml) was added until all solids haddissolved. The solution was then evaporated and the residue purified byMPLC [6% MeOH/CH₂Cl₂] as eluant] to give after trituration with diethylether, a white solid (0.025 g, 19%). MS: ESP⁺ (M+H)⁺=480.

¹H-NMR (300 MHz, DMSO-d6): δ=2.40 (d, 2H), 3.15 (m, 1H), 3.40 (m, 6H),3.79 (d, 2H), 3.98 (dd, 1H), 4.19 (s, 1H), 4.26 (dd, 1H), 4.34 (s, 1H),4.51 (m 2H), 5.15 (m, 1H), 5.93 (m, 1H), 6.43 (d, 1H), 7.40 (s, 1H),7.44 (s, 1H) and 8.74 (d, 1H).

EXAMPLE 305(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,3-propenoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Acryloyl chloride (0747 g, 0.67 ml, 8.25 mmol) in dichloromethane (5 ml)at 0° C. was treated with Reference Example 6 (0.682 g, 1.65 mmol) indichloromethane (5 ml) containing DMAP (0.201 g, 1.65 mmol) andtriethylamine (0.333 g, 0.46 ml, 3.39 mmol). The solution was stirredfor 1.5 h. The solution was washed with 2N HCL (10 ml), saturatedaqueous sodium hydrogen carbonate (10 ml), brine (10 ml), dried andevaporated. The residue was purified by MPLC [2% MeOH/CH₂Cl₂ as eluant]to give a white solid (0.471 g, 66%). MS: ESP⁺ (M+H)⁺=432.

¹H-NMR (300 MHz, DMSO-d6): δ=2.40 (d, 2H), 3.80 (d, 2H), 3.99 (dd, 1H),4.25 (m, 3H), 4.54 (m, 2H), 5.16 (m, 1H), 5.75 (d, 1H), 5.93 (s, 1H),6.20 (d, 1H), 6.45 (s, 1H), 6.88 (m, 1H), 7.42 (s, 1H), 7.48 (s, 1H) and8.75 (d, 1H).

REFERENCE EXAMPLE 195(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,3(R,S)-enoxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

n-Butyllithium (1.6M in hexanes) (0.65 ml, 1.04 mmol) was added to asolution of tert-butylhydroperoxide (5.5M in decane) (0.26 ml, 1.43mmol) in THF (5 ml) at −78 ° C. The mixture was stirred for 5 min. Asolution of the acrylamide. Example 30 (0.408 g, 0.95 mmol) in dry THF(2 ml) was added and stirring continued with the ice-bath removed untilthe temperature reached ca. 0° C. whereupon a water ice-bath was put inplace. Solid sodium sulfite (0.080 g, 0.30 mmol) was added and stirringcontinued for 15 min. Dichloromethane (10 ml) was added and the mixturefiltered through Celite and then evaporated. The residue was purified byMPLC [2% MeOH/CH₂Cl₂ as eluant] to give the product as a gum (0.378 g,89%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.46 (d, 2H), 2.87 (m, 1H), 3.00 (m, 1H),3.67-4.04 (m, 4H), 4.17 (s, 1H), 4.27 (t, 1H), 4.40 (d, 1H), 4.52 (m,2H), 5.16 (m, 1H), 5.95 (s, 1H), 6.43 (s, 1H), 7.40 (s, 1H), 7.45 (s,1H) and 8.76 (d, 1H). MS: ESP⁺ (M+H)⁺=448.

EXAMPLE 315(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-morpholinopropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 19 (0.073 g, 0.16 mmol) and morpholine (0.014 g, 0.014ml, 0.16 mmol) were refluxed in isopropanol (1 ml) for 1 h, and thenheated at 50° C. for 2 h. The solution was allowed to cool to RTovernight and then evaporated. The residue was purified by MPLC [4%MeOH/CH₂Cl₂ as eluant] to give a white foam (0.056 g, 66%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.41 (d, 2H), 2.60 (m, 6H), 3.60 (d, 4H),3.78 (m, 2H), 4.00 (dd, 1H), 4.17 (s, 1H), 4.26 (dd, 1H), 4.34 (s, 1H),4.56 (m, 3H), 5.04 (dd, 1H), 5.15 (m, 1H), 5.94 (s, 1H), 6.43 (d, 1H),7.40 (s, 1H), 7.44 (s, 1H) and 8.74 (s, 1H). MS: ESP⁺ (M+H)⁺=535.

REFERENCE EXAMPLE 205(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-(2-tert-butyldimethylsilyloxypyrrolidin-1-yl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 19 (0.149 g, 0.333 mmol) and2-tert-butyldimethylsilyloxy pyrrolidine (0.067 g, 0.333 mmol) inisopropanol (3 ml) were heated at 60 ° C. until TLC indicatedcompletion. The solution was evaporated and the residue was purified byMPLC [3→10% MeOH/CH₂Cl₂ as eluant] to give a colourless gum (0.173 g,80%). MS: ESP⁺ (M+H)⁺=649.

¹H-NMR (300 MHz, DMSO-d6): δ=0.00 (s, 6H), 0.82 (s, 9H), 1.50 (m, 1H),1.98 (m, 1H), 2.23-2.95 (m, 8H), 3.71 (s, 2H), 3.90 (dd, 1H), 4.08 (s,1H), 4.17 (t, 1H), 4.30 (s, 2H), 4.45 (m, 3H), 5.03 (m, 2H), 5.83 (s,1H), 6.33 (d, 1H), 7.30 (s, 1H), 7.34 (s, 1H) and 8.64 (s, 1H).

EXAMPLE 325(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-(2-hydroxypyrrolidino)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

The silyl ether Reference Example 20, (0.169 g, 0.26 mmol) in dry THF (5ml) at 0° C. was treated with tetrabutylammonium flouride (1.0 M in THF)(0.52 ml, 0.52 mmol) and then stirred for 5 h. The solution wasevaporated and the residue was purified by MPLC [3→6% MeOH/CH₂Cl₂ aseluant] to give a white solid(0.104 g, 75%).

¹H-NMR (300 MHz, DMSO-d6): δ=1.54 (s, 1H), 1.92 (m, 1H), 2.30 (m, 3H),2.50-2.88 (m, 5H), 3.63 (m, 2H), 3.89 (dd, 1H), 4.13 (m, 4H), 4.45 (m,3H), 4.65 (s, 1H), 5.05 (m, 2H), 5.86 (s, 1H), 6.35 (d, 1H), 7.34 (s,1H), 7.38 (s, 1H) and 8.68 (d, 1H). MS: ESP⁺ (M+H)⁺=535.

REFERENCE EXAMPLE 215(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-phenyl-1,3-dioxan-5(R,S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)-oxazolidin-2-one

To a stirred solution of Reference Example 11 (0.368 g, 0.93 mmol) theacid, 5-carboxy-2-phenyl-1,3-dioxan (JOC, 1997, 62, 4029) (0.232 g, 1.12mmol), triethylanine (0.094 g, 0.129 ml, 0.93 mmol) and HOBT (0.151 g,1.12 mmol) in dichloromethane (11 ml) was added EDC (0.215 g, 1.12mmol). The mixture was stirred for 20 h and then the solution was washedwith 2N HCL (10 ml), brine (10 ml), dried and evaporated. The residuewas purified by MPLC [2% MeOH/CH₂Cl₂ as eluant] to give an oil (0.475 g,93%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.62 (m, 2H), 3.48 (m, 1H), 3.70 (m, 1H),3.82 (m, 1H), 3.93-4.60 (m, 10H), 5.14 (m, 1H), 5.60 (s, 1H), 6.08 (s,1H), 6.42 (d, 1H), 7.46 (m, 8H) and 8.76 (d, 1H). MS: ESP⁺ (M+H)⁺=550.

EXAMPLE 335(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-hydroxy-2-hydroxymethyl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Reference Example 21(0.475 g, 0.87 mmol) was stirred in 80% aceticacid/water (10 ml) for 24 h. The precipitate slowly dissolved. Thesolution was evaporated and purified by MPLC [5% MeOH/CH₂Cl₂ as eluant]to give after trituration with diethyl ether, a white powder (0.284 g,71%). MS: ESP⁺ (M+H)⁺=462.

¹H-NMR (300 MHz, DMSO-d6): δ=2.51 (d, 2H), 3.15 (m, 1H)). 3.58 (m, 4H),3.78 (m, 2H), 3.99 (dd, 1H), 4.26 (d, 2H), 4.28 (t, 1H), 4.54 (m, 2H),4.65 (m, 2H), 5.15 (m, 1H), 6.06 (s, 1H), 6.43 (d, 1H), 7.35-7.63 (m,3H) and 8.76 (d, 1H).

REFERENCE EXAMPLE 225(R,S)-Carboxymethyl-2,2-dimethyl-4-oxo-1,3-dioxolane

(D,L)-Malic acid (12.41 g, 92.6 mmol) and PTSA (2.32 g, 9.26 mmol) in2,2-dimethoxypropane (35 ml) were stirred for 5 days. The solution wasevaporated and the residue was purified by MPLC [25% EtOAc/isohexane aseluant] to give a colurless gum (11.48 g, 71%).

¹H-NMR (300 MHz, DMSO-d6): =1.58 (s, 3H), 1.60 (s, 3H), 2.82 (m, 2H),4.85 (t, 1H) and 12.64 (s, 1H).

EXAMPLE 345(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5(R,S)-ylacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)-oxazolidin-2-one

To a stirred solution of Reference Example 11 (0.384 g, 0.97 mmol), theacid (Reference Example 22) (0.203 g, 1.17 mmol), triethylamine (0.098g, 0.135 ml, 0.97 mmol) and HOBT (0.158 g, 1.17 mmol) in dichloromethane(11 ml) was added EDC (0.225 g, 1.17 mmol). The mixture was stirred for60 h and then the solution was dried and evaporated. The residue waspurified by MPLC [3% MeOH/CH₂Cl₂ as eluant] to give an oil (0.356 g,71%). MS: ESP⁺ (M+H)⁺=516.

¹H-NMR (300 MHz, DMSO-d6): δ=1.57 (s, 3H), 1.60 (s, 3H), 2.53 (d, 2H),3.02 (m, 2H), 3.70 (m, 2H), 4.00 (dd, 1H), 4.19 (d, 2H), 4.25 (t, 1H),4.52 (m, 2H), 4.89 (t, 1H), 5.15 (m, 1H), 6.05 (s, 1H), 6.44 (d, 1H),7.36-7.63 (m, 3H) and 8.75 (d, 1H).

EXAMPLE 355(R-Isoxazol-3-yloxymethyl-3-(4-(1-(3-carboxy-3(R,S)-hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Example 34 (0.345 g, 0.67 mmol) was stirred in 80% acetic acid/water (5ml) for 20 h. The acetonide slowly dissolved and then the product slowlyprecipitated, Diethyl ether (10 ml) was added and the solid collected byfiltration to give a white solid (0.300 g, 94%). MS: ESP⁺ (M−H)⁺=474.

¹H-NMR (300 MHz, DMSO-d6): δ=2.52 (d, 2H), 2.80 (m, 2H), 3.71 (s, 2H),4.00 (dd, 1H), 4.20 (d, 2H), 4.28 (t, 1H), 4.41 (t, 1H), 4.55 (m, 2H),5.15 (m, 1H), 6.08 (s, 1H), 6.46 (d, 1H), 7.35-7.62 (m, 3H) and 8.77 (d,1H).

REFERENCE EXAMPLE 235(R,S)-Methylaminocarbonylmethyl-2,2-dimethyl-4-oxo-1,3-dioxolane

The acid Reference Example 22 (2.84 g, 16.32 mmol) was heated underreflux in thionyl chloride (25 ml) for 1.25 h under nitrogen. Thesolution was evaporated and azeotroped with toluene (2×). A portion ofthe crude acid chloride (5.44 mmol) was dissolved in dichloromethane (5ml), treated with methylamine (2.0 M in THF) (5.44 ml, 10.88 mmol) andstirred for 1.5 h. The resultant suspension was diluted, washed with 2NHCL (10 ml), brine (10 ml), dried and evaporated. The residue waspurified by MPLC [5% MeOH/CH₂Cl₂ as eluant] to give a pale tan solid(0.393 g, 39%).

¹H-NMR (300 MHz, DMSO-d6): δ=1.56 (s, 6H), 2.66 (m, 2H), 2.68 (s, 3H),4.82 (t, 1H) and 7.95 (s, 1H). MS: ESP⁺ (M+H)⁺=188.

REFERENCE EXAMPLE 24 2(R,S)-hydroxy-3-methylaminocarbonylpropanoic Acid

The amide Reference Example 23 (0.392 g, 2.10 mmol) was stirred in MeOH(4 ml) containing PTSA (0.053 g, 0.21 mmol) for 5 days. The solution wasevaporated and the residue was purified by MPLC [5% MeOH/CH₂Cl₂ aseluant] to give the methyl ester (0.284 g). This was dissolved inMeOH/water (3:1) (4 ml), treated with lithium hydroxide (0.370 g, 8.82mmol) and stirred for 15 min. The mixture was diluted with water (20ml), treated with Dowex 50W-X8(H), stirred for 5 min filtered andevaporated to in vacuo to give a gum (0.216 g, 83%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.38 (dd, 1H), 2.49 (dd, 1H), 2.64 (s, 3H),3.54 (br s, 1H), 4.34 (m, 1H), 7.87 (m, 1H) and 12.53 (br s, 1H). MS:ESP⁻ (M−H)⁺=146.

EXAMPLE 365(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-methylaminocarbonylpropanoyl)-1,2,5,6-tetrahydrolpyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 11 (0.175 g, 0.44 mmol), theacid Reference Example 24 (0.078 g, 0.53 mmol), triethylamine (0.044 g,0.061 ml, 0.44 mmol) and HOBT (0.072 g, 0.53 mmol) in dichloromethane (6ml) was added EDC (0.102 g, 0.53 mmol). The mixture was stirred for 16h. TLC indicated incomplete reaction and more acid (0.138 g, 0.94 mmol),HOBT (0.127 g, 0.94 mmol) and EDC (0.180 g, 0.94 mmol) was added, After5 h the solution was evaporated. The residue was purified by MPLC [5→15%MeOH/CH₂Cl₂ as eluant] to give an oil (0.070 g, 33%). MS: ESP⁺(M+H)⁺=489.

¹H-NMR (300 MHz, DMSO-d6): δ=2.44 (m, 4H), 2.63 (d, 3H), 3.66 (m, 1H),3.77 (s, 1H), 4.00 (dd, 1H), 4.22 (m, 3H), 4.54 (m, 2H), 4.79 (m, 1H),5.15 (m, 1H), 5.38 (d, 1H), 6.10 (s, 1H), 6.48 (d, 1H), 7.35-7.64 (m,3H), 7.88 (s, 1H) and 8.79 (d, 1H).

EXAMPLE 375(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3(R,S)-hydroxy-3-methylaminocarbonylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred solution of Example 35 (0.070 g, 0.15 mmol) and HOBT (0.020g, 0.15 mmol) in dichloromethane (4 ml) was added EDC (0.028 g, 0.15mmol) and then methylamine (2.0M in THF) (0.23 ml, 0.45 mmol). Themixture was stirred for 22 h and then purified by MPLC [5% MeOH/CH₂Cl₂as eluant] to give after trituration with diethyl ether a white solid(0.01 g, 14%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.48 (d, 2H), 2.65 (d, 3H), 2.69 (m, 2H),3.69 (m, 2H), 3.94 (dd, 1H), 4.17 (m, 2H), 4.20 (t, 1H), 4.30 (m, 1H),4.48 (m, 2H), 5.08 (m, 1H), 5.61 (m, 1H), 6.00 (s, 1H), 6.39 (d, 1H),7.38 (m, 2H), 7.50 (d, 1H), 7.78 (m, 1H) and 8.70 (d, 1H). MS: ESP⁺(M+H)⁺=489.

REFERENCE EXAMPLE 255(R,S)-(2-(2-Methoxyethoxy)ethoxy)carbonylmethyl-2,2-dimethyl-4-oxo-1,3-dioxolane

The acid (Reference Example 22) (2.75 g, 15.80 mmol) in dichloromethane(15 ml) at 0° C. was treated with oxalyl chloride (2.99 g, 2.1 ml, 23.71mmol) and stirred with a drop of DMF for 2 h. The solution wasevaporated, A portion of the crude acid chloride (1.90 g, 9.84 mmol) indichloromethane (20 ml) at 0° C. containing 4-DMAP (1.20 g, 9.84 mmol)was treated with 2-(2-methoxyethoxy)ethanol (4.72 g, 4.70 ml, 39.36mmol) and stirred overnight. The solution was washed with 2N HCL (2×15ml), brine (10 ml), dried and evaporated. The residue was purified byMPLC [3% MeOH/CH₂Cl₂ as eluant] to give an oil (0.785 g, 29%).

¹H-NMR (300 MHz, DMSO-d6): δ=1.54 (s, 6H), 2.89 (t, 2H), 3.27 (s, 3H),3.43 (m, 2H), 3.53 (m, 2H), 3.60 (m, 2H), 4.19 (m, 2H) and 4.84 (t, 1H).

REFERENCE EXAMPLE 262(R,S)-Hydroxy-3-(2-(2-methoxyethoxy)ethoxy)carbonyl-propanoic Acid

Reference Example 25 (0.785 g, 2.84 mmol) was stirred in 80% aceticacid/water (5 ml) for 5 days. The solution was evaporated to give anorange oil (0.600 g, 89%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.54 (dd, 1H), 2.72 (dd, 1H), 3.26 (s, 3H),3.42 (m, 2H), 3.52 (m, 2H), 3.59 (m, 2H), 4.13 (m, 2H), 4.30 (m, 1H),5.49 (s, 1H) and 12.58 (s, 1H). MS: ESP⁻ (M−H)⁺=235.

EXAMPLE 385(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-(2-(2-methoxyethoxy)ethoxy)carbonylpropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 11 (0.329 g, 0.79 mmol), theacid Reference Example 26 (0.225 g, 0.95 mmol), triethylamine (0.079 g,0.110 ml, 0.79 mmol) and HOBT (0.129 g, 0.95 mmol) in dichloromethane(10 ml) was added EDC (0.183 g, 0.95 mmol). The mixture was stirred for48 h and then the solution was dried and evaporated. The residue waspurified by MPLC [5% MeOH/CH₂Cl₂ as eluant] to give a white solid (0.283g, 62%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.52 (d, 2H), 2.60 (dd, 1H), 2.85 (dd, 1H),3.31 (s, 3H), 3.50 (m, 2H), 3.60 (m, 2H), 3.68 (m, 2H), 3.80 (m, 2H),4.00 (dd, 1H), 4.10-4.40 (m, 5H), 4.54 (m, 2H), 4.76 (m, 1H), 5.15 (m,1H), 5.64 (m, 1H), 6.09 (s, 1H), 6.43 (d, 1H), 7.43 (m, 2H), 7.58 (d,1H) and 8.75 (d, 1H). MS: ESP⁺ (M+H)⁺=578.

EXAMPLE 395(R)-Isoxazol-3-yloxymethyl-3-(4-morpholino-3-fluoro-phenyl)oxazolidin-2-one

Prepared by the general method of Example 1 using as starting material5(R)-hydroxymethyl-3-(4-morpholino-3-fluoro-phenyl)oxazolidin-2-one(WO95/07271; 300 mg, 1.01 mmol), 3-hydroxyisoxazole (95 mg, 1.12 mmol),diisopropylazodicarboxylate (225 mg, 1.11 mmol) and triphenylphosphine(305 mg, 1.16 mmol) in THF (5 ml). Purified by flash chromatography(Merck 9385 silica. EtOAc/isohexane (7/3)) to give the title compound(254 mg, 69%) as a colourless solid.

¹H-NMR (300 MHz, CDCl₃): δ=3.05 (m, 4H), 3.88 (m, 4H), 3.94 (dd, 1H),4.14 (t, 1H), 4.47-4.62 (m, 2H), 5.01 (m, 4H), 6.00 (d, 1H), 6.94 (t,1H), 7.15 (dd, 1H), 7.46 (d, 1H), 8.15 (d, 1H). MS: ESP⁺ (M+H)⁺=364.

REFERENCE EXAMPLE 27 5(R)-Hydroxymethyl-3-(4-iodophenyl)oxazolidin-2-one

3-Phenyl-oxazolidin-2-one (U.S. Pat. No. 4,705,799; 3.0 g, 15.5 mmol),silver trifluoroacetate (4.5 g, 20.4 mmol) and iodine (4.7 g, 18.5 mmol)in a mixture of acetonitrile (30 ml) and chloroform (30 ml) were stirredat room temperature for 72 hr then a further 1 g silver trifluoroacetateand 1 g iodine added and stirring continued for 18 hr. The mixture wasthen filtered and the filtrate evaporated to give an orange oil whichwas purified by flash chromatography (Merck 9385 silica, 5%MeOH/dichloromethane) followed by recrystallisation from EtOAc/isohexaneto give the title compound (1.85 g, 38%) as a colourless solid. MS: ESP⁺(M+H)⁺=320.

¹H-NMR (300 MHz, DMSO-d6): δ=3.53 (m, 1H), 3.47 (m, 1H), 3.78 (dd, 1H),4.05 (t, 1H), 4.69 (m, 1H), 5.18 (t, 1H), 7.38 (d, 2H), 7.69 (d, 2H).

REFERENCE EXAMPLE 285(R)-Isoxazol-3-yloxymethyl-3-(4-iodophenyl)oxazolidin-2-one

Prepared by the general method of Example 1 using (1.85 g, 5.80 mmol),3-hydroxyisoxazole (0.55 g, 6.47 mmol), diisopropylazodicarboxylate(1.29 g, 6.39 mmol) and triphenylphosphine (1.75 g, 6.68 mmol) in THF(30 ml). Purified by flash chromatography (Merck 9385 silica,EtOAc/isohexane (1/1)) to give the title compound (1.45 g, 64%) as acolourless solid. MS: ESP⁺ (M+H)⁺=387.

¹H-NMR (300 MHz, CDCl₃) δ=3.94 (dd, 1H), 4.13 (t, 1H), 4.46-4.61 (m,2H), 5.03 (m, 1H), 6.00 (d, 1H), 7.34 (d, 2H), 7.69 (d, 2H), 8.15 (d,1H).

REFERENCE EXAMPLE 295(R)-Isoxazol-3-yloxymethyl-3-(4-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydrolpyrid-4-yl)phenyl)oxazolidin-2-one

Lithium chloride (1.0 g, 23.6 mmol), triphenylarsine (0.95 g, 3.10 mmol)and tris(dibenzylideneacetone)dipalladium(0) (0.7 g, 0.76 mmol) wereadded at room temperature, under an atmosphere of nitrogen, to a stirredsolution of Reference Example 28 (3.0 g, 7.77 mmol) in DMF (50 ml,degassed). The resulting mixture was stirred for 15 min thenN-tert-butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine (3.0g, 8.67 mmol ; prepared fromN-tert-butoxycarbonyl-4-triflate-1,2,5,6-tetrahydropyridine (WO97/30995)reacted with hexamethyltin using a Pd(0) catalyst) in DMF (10 ml) addedin one go. The reaction was stirred and heated at 50°-55° C. for 3 hr,cooled to room temperature then treated with a 2N aqueous solution ofpotassium fluoride (8 ml). After stirring for 30 min the solvent wasevaporated (50°, high vac.) then the residue partitioned betweendichloromethane and water, filtered and the dichloromethane layerseparated, Washed with water (2X) and sat. brine, dried over magnesiumsulfate and evaporated to an orange viscous oil. Purified by flashchromatography (Merck 9385 silica, EtOAc/isohexane (3/2)) to give thetitle compound as a pale yellow solid. MS: ESP⁺ (M+H)⁺=442.

REFERENCE EXAMPLE 305(R)-Isoxazol-3-yloxymethyl-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-phenyl)oxazolidin-2-one

Reference Example 29 (2.1 g, 4.76 mmol) in MeOH (30 ml) (partialsolution) was treated at room temperature with an approx. 4M solution ofHCl in ethanol and the resulting mixture stirred 4 hr then left to stand16 hr. Diethyl ether (50 ml) was then added and the resulting paleyellow solid filtered, washed with ether and dried: 1.71 g (95%yield)—title compound as the hydrochloride salt.

¹H-NMR (300 MHz, DMSO-d6): δ=2.66 (m, 2H), 3.30 (m, partially obscuredby DMSO, 2H), 3.73 (m, 2H), 3.92 (dd, 1H), 4.20 (t, 1H), 4.41-4.53 (m,2H), 5.08 (m, 1H), 6.16 (m, 1H), 6.35 (d, 1H), 7.49 (d, 2H), 7.57 (d,2H), 8.68 (d, 1H), 9.30 (s(br), 2H). MS: ESP⁺ (M+H)⁺=342. Free baseisolated by treating with aqueous sodium hydroxide solution andextraction with dichloromethane to give title compound as a yellowsolid.

REFERENCE EXAMPLE 315(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

1,3 Dicyclohexylcarbodiimide (298 mg, 1.45 mmol) was added in one go atroom temperature to a stirred solution of(R)-2,3-O-isopropylideneglyceric acid (235 mg, 1.40 mmol 87% purity) and1-hydroxybenzotriazole (218 mg, 1.42 mmol) in dichloromethane (15 ml).The resulting suspension was stirred 1 hr then a further 5 mldichloromethane was added followed by Reference Example 30 (500 mg, 1.47mmol), stirred 16 hr, filtered and the filtrate washed with water andsat. brine. Purified by flash chromatography (Merck 9385 silica, 2.5%MeOH/dichloromethane) to give the title compound (395 mg, 57%) as acolourless solid. MS: ESP⁺ (M+H)⁺=470.

REFERENCE EXAMPLE 325(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

Prepared by the general method of Reference Example 31, using ReferenceExample 30 (500 mg, 1.47 mmol), 1,3 dicyclohexylcarbodiimide (298 mg,1.45 mmol), (S)-2,3-O-isopropylideneglyceric acid (235 mg, 1.40 mmol 87%purity) and 1-hydroxybenzotriazole (218 mg, 1.42 mmol) indichloromethane (15 ml). Purified by flash chromatography (Merck 9385silica, 2.5% MeOH/dichloromethane) to give the title compound (408 mg,59%) as a colourless solid. MS: ESP⁺ (M+H)⁺=470.

EXAMPLE 405(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

Prepared by the general method of Example 4 using Reference Example 31(395 mg, 0.84 mmol) in 1N hydrochloric acid (3 ml) and THF (9 ml).Purified by flash chromatography (Merck 9385 silica, 8%MeOH/dichloromethane) to give the title compound (203 mg, 56%) as acolourless solid, mp=138°-144° C.

¹H-NMR (300 MHz, DMSO-d6): δ=2.40-2.56 (m, partially obscured by DMSO,2H), 3.40-3.63 and 3.63-3.88 (m, 4H), 3.92 (dd, 1H), 4.11 (m, 2H), 4.20(t, 1H), 4.30-4.54 (m, 3H), 4.68 (m, 1H), 4.92 (m, 1H), 5.07 (m, 1H),6.15 (m, 1H), 6.37 (d, 1H), 7.46 (d, 2H), 7.53 (d, 2H), 8.68 (d, 1H).MS: ESP⁺ (M+H)⁺=430.

EXAMPLE 415(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

Prepared by the general method of Example 4 using Reference Example 32(408 mg, 0.87 mmol) in 1N hydrochloric acid (3 ml) and THF (9 ml).Purified by flash chromatography (Merck 9385 silica, 8%MeOH/dichloromethane) to give the title compound (124 mg, 33%) as acolourless solid, mp=200°-202° C.(dec).

¹H-NMR (300 MHz, DMSO-d6): δ=2.38-2.56 (2H), 3.20-3.40 (m, partiallyobscured by DMSO, 2H), 3.54 (m, 1H), 3.64-3.85 (m, 1H), 3.92 (dd, 1H),4.12 (m, 2H), 4.20 (t, 1H), 4.30-4.55 (m, 3H), 5.07 (m, 1H), 6.15 (m,1H), 6.37 (d, 1H), 7.46 (d, 2H), 7.53 (d, 2H), 8.66 (d, 1H). MS: ESP⁺(M+H)⁺=430.

EXAMPLE 425(R)-Isoxazol-3-yloxymethyl-3-(4-methylthiophenyl)oxazolidin-2-one

Prepared by the general method of Example 1 using5(R)-hydroxymethyl-3-(4-methylthiophenyl)oxazolidin-2-one (650 mg, 2.72mmol ; prepared from the reaction of 4-methylthioaniline and(R)-glycidyl butyrate), 3-hydroxyisoxazole (243 mg, 2.86 mmol),diisopropylazodicarboxylate (577 mg, 2.86 mmol) and triphenylphosphine(770 mg, 2.94 mmol) in THF (10 ml). Purified by flash chromatography(Merck 9385 silica, EtOAc/isohexane (1/1)) to give the title compound507 mg, 61%) as a colourless solid. MS: ESP⁺ (M+H)⁺=307.

¹H-NMR (300 MHz, CDCl₃): δ=2.47 (s, 3H), 3.97 (dd, 1H), 4.15 (t, 1H),4.47-4.62 (m, 2H), 5.02 (m, 1H), 6.00 (d, 1H), 7.30 (d, 2H), 7.49 (d,2H), 8.14 (d, 1H).

EXAMPLE 435(R)-Isoxazol-3-yloxymethyl-3-(4-methylsulfinylphenyl)oxazolidin-2-oneand Example 44:5(R)-Isoxazol-3-yloxymethyl-3-(4-methylsulfonylphenyl)oxazolidin-2-one

3-Chloroperoxybenzoic acid (282 mg,70% strength, 1.14 mmol) was added toa solution of Example 42 (340 mg, 1.11 mmol) in dichloromethane (10 ml)at −40° C. The reaction was stirred at −30° to −40° C. for 3 hr thendiluted with more dichloromethane (10 ml), washed with aq. sodiumbisulfite solution, sat. aq. sodium bicarbomate solution and water,dried over magnesium sulfate and evaporated to a colourless oil.Purified by flash chromatography (Merck 9385 silica, 5%MeOH/dichloromethane) to give Example 43 (275 mg, 77%) and Example 44(31 mg), both as colourless solids.

Example 43: MS: ESP⁺ (M+H)⁺=323.

¹H-NMR (300 MHz, CDCl₃): δ=2.73 (s, 3H), 4.06 (dd, 1H), 4.22 (t, 1H),4.50-4.65 (m, 2H), 5.08 (m, 1H), 6.00 (d, 1H), 7.69 (d, 2H), 7.77 (d,2H), 8.15 (d, 1H).

Example 44: MS: ESP⁺ (M+H)⁺=339.

¹H-NMR (300 MHz, DMSO-d6) δ=3.14 (s, 3H), 3.98 (dd, 1H), 4.26 (t, 1H),4.43-4.54 (m, 2H), 5.10 (m, 1H), 6.34 (d, 1H), 7.80 (d, 2H), 7.92 (d,2H), 8.66 (d, 1H).

EXAMPLE 455(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-(1-imidazoyl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one

Reference Example 19 (200 mg, 0.45 mmol) and 1H-imidazole (34 mg, 0.50mmol) in 2-propanol (2 ml)were refluxed for 8 hr then the resultingsolution cooled to room temperature and purified by flash chromatography(Merck 9385 silica, 10% MeOH/dichloromethane) to give the title compound(83 mg, 36%) as a colourless solid.

¹H-NMR (300 MHz, DMSO-d6) δ=2.25-2.50 (m, 2H), 3.55-3.83 (m, 2H), 3.95(dd, 1H), 4.00-4.40 (m, 5H), 4.44-4.56 (m, 2H), 4.56-4.68 (m, 1H), 5.11(m, 1H), 5.65 (d) and 5.75 (d) (1H), 5.87 (m, 1H), 6.37 (d, 1H), 6.85(m, 1H), 7.15 (m, 1H), 7.36 (d, 2H), 7.58 (m, 1H), 8.68 (d, 1H). MS:ESP⁺ (M+H)⁺=516.

EXAMPLE 465(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S)-hydroxy-3-(1,2,4-triazol-1-yl)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one

Prepared by the general method of Example 45 using Reference Example 19(200 mg, 0.45 mmol) and 1H-1,2,4-Triazole (35 mg, 0.50 mmol) in2-propanol (2 ml). Purified by flash chromatography (Merck 9385 silica,10% MeOH/dichloromethane) to give the title compound (84 mg, 36%) as acolourless solid. MS: ESP⁺ (M+H)⁺=517.

¹H-NMR (300 MHz, DMSO-d6): δ=2.25-2.50 (m, 2H), 3.55-3.85 (m, 2H), 3.95(dd, 1H), 4.00-4.40 (m, 5H), 4.40-4.55 (m, 2H), 4.68-4.82 (m, 1H), 5.12(m, 1H), 5.77 (d) and 5.81 (d) (1H), 5.90 (m, 1H), 6.77 (d, 1H), 7.35(d, 2H), 7.95 (s, 1H), 8.44 (s, 1H), 8.68 (d, 1H).

EXAMPLE 475R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-acetoxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

(S)-2-Acetoxypropionyl chloride (126 mg, 0.84 mmol) was added dropwiseat room temperature to a stirred suspension of Reference Example 11 (300mg, 0.76 mmol) and N,N diisopropyl ethylamine (210 mg, 1.63 mmol) indichloromethane (10 ml). The reaction was stirred at room temperaturefor 2 hr then purified by flash chromatography (Merck 9385 silica, 2.5%MeOH/dichloromethane) to give the title compound (322 mg, 90%) as acolourless solid. MS: ESP⁺ (M+H)⁺=474.

¹H-NMR (300 MHz, CDCl₃): δ=1.48 (s) and 1.51 (s) (3H), 2.14 (s, 3H),2.50-2.74 (m, 2H), 3.68 (m) and 3.96 (m) (3H), 4.05-4.36 (m, 3H),4.47-4.62 (m, 2H), 5.04 (m, 1H), 5.35-5.55 (m, 1H), 5.97 (m, 1H), 6.00(d, 1H), 7.20-7.30 (m, 2H), 7.45 (d, 1H), 8.15 (d, 1H).

EXAMPLE 485(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Example 47 (200 mg, 0.42 mmol) in 10 ml of a saturated solution ofammonia in MeOH was stirred at room temperature for 18 hr then cooled inice-water before filtering the resulting colourless solid. Washed withice-cold MeOH and diethyl ether then dried to give the title compound(156 mg, 86%). MS: ESP⁺ (M+H)⁺=432.

¹H-NMR(300 MHz, DMSO-d6): δ=1.23 (s) and 1.25 (s) (3H), 2.33-2.50 (m,2H), 3.52-3.85 (m, 2H), 3.93 (dd, 1H), 4.02-4.38 (m, 3H), 4.40-4.60 (m,2H), 4.85-5.00 (m, 1H), 5.11 (m, 1H), 6.03 (m, 1H), 6.38 (d, 1H), 7.33(dd, 1H), 7.41 (t, 1H), 7.52 (dd, 1H), 8.68 (d, 1H).

EXAMPLE 495(R)-Isoxazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 6 using Reference Example 11(300 mg, 0.76 mmol), acetoxyacetyl chloride (114 mg, 0.83 mmol),triethylamine (88 mg, 0.87 mmol) and 4-(dimethylamino) pyridine (25 mg)in dichloromethane 10 ml). Purified by chromatography (bond elut(silica, 10 g), 1-2% MeOH/dichloromethane) to give the title compound(230 mg, 66%) as a colourless solid. MS: ESP⁺ (M+H)⁺=460.

¹H-NMR (300 MHz, CDCl₃): δ=2.20 (s, 3H), 2.50-2.66 (m, 2H), 3.60 (t) and3.83 (t) (2H), 3.96 (dd, 1H), 4.10 (m) and 4.24 (m, 2H), 4.15 (t, 1H),4.50-4.64 (m, 2H), 4.77 (s) and 4.81 (s) (2H), 5.04 (m, 1H), 5.90-6.00(m, 1H), 6.00 (d, 1H), 7.21-7.30 (m, 2H), 7.45 (d, 1H), 8.15 (d, 1H).

EXAMPLE 505(R)-Isoxazol-3-yloxymethyl-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 48 using Example 49 (170 mg,0.37 mmol) in 10 ml of a saturated solution of ammonia in MeOH to givethe title compound (121 mg, 79%) as a colourless solid. MS: ESP⁺(M+H)⁺=418.

¹H-NMR (300 MHz, CDCl₃): δ=2.52-2.62 (m, 2H), 3.48 (t) and 3.65 (t)(2H), 3.87 (t) and 3.95 (m) (3H), 4.16 (t, 1H), 4.22 (dd, 1H), 4.30 (m,1H), 4.48-4.62 (m, 2H), 5.04 (m, 1H), 5.92 (m) and 6.00 (m) (d, 1H),6.00 (d, 1H), 7.20-7.30 (m, 2H), 7.43 (d, 1H), 8.15 (d, 1H).

EXAMPLE 515(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(3-pyridin-1-iummethyl-benzoyloxy)-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-oneChloride

Example 12 (0.40 g, 0.89 mmol) was suspended in dichloromethane (20 ml),and pyridine (0.07 g, 0.89 mmol), 4-dimethylaminopyridine (0.2 g) wasadded, 3-chloromethylbenzoyl chloride was added dropwise and thereaction mixture was stirred at room temperature for 2 hr. The resultingsolution was washed with water, dried (MgSO₄) and purified bychromatography (Merck 9385 silica, 5-10% MeOH in CH₂Cl₂) to give thetitle compound as a pale yellow solid (0.30 g, 42%) after triturationwith diethyl ether.

¹H-NMR (300 MHz, DMSO-d6): δ=2.43 (partially obscured by DMSO, 2H),3.64-4.52 (m, 10H), 4.74 (m, 1H), 5.08 (m, 1H), 5.98 (m, 3H), 6.37 (m,1H), 7.35 (m, 2H), 7.46-7.63 (m, 2H), 7.81 (m, 1H), 8.00 (m, 1H), 8.16(m, 2H), 8.54-8.65 (m, 2H), 8.68 (m, 1H), 9.26 (M, 2H). MS: ESP⁺(M)⁺=643.

EXAMPLE 525(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(3-chloromethylbenzoyloxy)-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Example 12 (0.50 g, 1.12M) was suspended in dichloromethane (20 ml), andtriethylamine (0.11 g, 0.16 mmol) was added. 3-chloromethylbenzoylchloride was added dropwise and the reaction mixture was stirred at roomtemperature for 2 hr. The resulting solution was washed with water,dried (MgSO₄) and purified by chromatography (Merck 9385 silica, 4-5%MeOH in CH₂Cl₂) to give the title compound as a yellow solid (0.46 g,69%) after trituration with diethyl ether and isohexane, also containingsome di-substituted derivative.

¹H-NMR (300 MHz, DMSO-d6): δ=2.45 (partially obscured by DMSO, 2H),3.65-3.98 (m, 3H), 3.98-4.25 (m, 2H), 4.31-4.55 (m, 4H), 4.70-4.87 (m,4H), 5.07 (m, 1H), 5.71 (m, 1H), 6.04 (m, 1H), 6.41 (m, 1H), 7.28-7.46(m, 2H), 7.46-7.59 (m, 2H), 7.71 (m, 1H), 7.87-8.12 (m, 2H), 8.72 (m,1H). MS: ESP⁺ (M+H)⁺=600.

EXAMPLE 535(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(3-morpholinomethylbenzoyloxy)-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Example 52 (0.01 g, 0.17 mmol), was stirred in DMF (3 ml), sodium iodide(ca, 10 mg) and morpholine (0.07 g, 0.67 mmol) was added and thereaction mixture was heated at 50° C. for 5 hr. The DMF was removed byevaporation and the residue was taken up in dichloromethane, washed withwater, dried (MgSO₄) and purified by chromatography (Merck 9385 silica,5-10% MeOH in CH₂Cl₂) to give the title compound as an off white solid(65 mg, 60%), after trituration with isohexane and diethyl ether.

¹H-NMR (300 MHz, DMSO-d6): δ=2.27 (m, 4H), 2.41 (partially obscured byDMSO, 2H), 3.40-3.59 (m, 6H), 3.63-3.98 (m, 3H), 3.98-4.57 (m, 7H), 4.74(m, 1H), 5.08 (m, 1H), 5.67 (m, 1H), 6.04 (m, 1H), 6.39 (m, 1H),7.28-7.64 (m, 5H), 7.88 (m, 2H), 8.72 (m, 1H). MS: ESP⁺ (M+H)⁺=651.

EXAMPLE 545(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(3-(4-methylpiperazinomethyl)benzoyloxy)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 53, using Example 52 (0.10 g,0.17 mmol), sodium iodide (ca, 10 mg) and N-methylpiperazine (0.07 g,0.67 mmol). Purified by chromatography (Merck 9385 silica, 5-10% MeOH inCH₂Cl₂−10% MeOH+1% ammonia in CH₂Cl₂), to give the title compound aswhite solid (55 mg, 50%) after trituration with isohexane.

¹H-NMR (300 MHz, DMSO-d6): δ=2.44 (partially obscured by DMSO, 5H), 2.62(m, 4H), 3.21-3.35 (partially obscured by water, 4H), 3.55 (m, 2H),3.65-3.84 (m, 2H), 3.92 (dd, 1H), 4.08-4.25 (m, 2H), 4.34 (m, 1H), 4.45(m, 4H), 4.75 (m, 1H), 5.08 (m, 1H), 5.62 (m, 1H), 6.02 (broad s, 1H),6.36 (m, 1H), 7.28-7.60 (m, 5H), 7.88 (m, 2H), 8.68 (m, 1H). MS: ESP⁺(M+H)⁺=664.

EXAMPLE 555(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-(3-di-n-butylaminomethylbenzoyloxy)propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 53, using Example 52 (0.10 g,0.17 mmol), sodium iodide (ca, 10 mg) and di-N-butylamine (0.07 g, 0.67mmol). Purified by chromatography Merck 9385 silica, 5-10% MeOH inCH₂Cl₂−10% MeOH+1% ammonia in CH₂Cl₂), to give the title compound aswhite solid (54 mg, 47%) after trituration with isohexane.

¹H-NMR (300 MHz, DMSO-d6): δ=0.71-0.89 (m, 6H), 1.13-1.43 (m, 8H), 2.31(partially obscured by DMSO, 6H), 3.33 (partially obscured by water,2H), 3.42-3.59 (m, 2H), 3.67-3.97 (m, 3H), 3.97-4.56 (m, 5H), 4.74 (m,1H), 5.08 (m, 1H), 5.67 (m, 1H), 6.03 (broad s, 1H), 6.38 (m, 1H),7.28-7.63 (m, 5H), 7.87 (m, 2H), 8.69 (m, 1H). MS: ESP⁺ (M+H)⁺=693.

EXAMPLE 565(R)-Isoxazol-3-yloxymethyl-3-(4-(1-n-propyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Reference Example 11 (500 mg, 1.26 mmol) was stirred in MeOH (10 ml) andglacial acetic acid (˜0.5 ml) was added to pH4. Propanal (80.7 mg, 1.39mmol) was added dropwise, and the reaction was stirred for 40 minutes.To the stirred solution, sodium cyanoborohydride was added (83.4 mg,1.33 mmol) portionwise. The reaction was stirred for a further 30minutes at room temperature. The reaction was quenched with 10% NaOAcand extracted with dichloromethane and the combined organic phases weredried over MgSO₄ and evaporated under reduced pressure. The resultingbrown oil was triturated with ether to yield the title compound as anorange solid (300.6 mg, 59%). MS: ESP+ (M+H)⁺=402.

¹H-NMR (300 MHz, DMSO-d6): δ=0.85 (t, 3H), 1.46 (m, 2H), 2.32 (t, 2H),2.40 (broad s, 2H), 2.57 (t, 2H), 3.04 (d, 2H), 3.93 (dd, 1H), 4.19 (t,1H), 4.48 (m, 2H), 5.08 (m, 1H), 5.97 (broad s, 1H), 6.37 (d, 1H),7.29-7.40 (m, 2H), 7.49 (dd, 1H), 8.70 (d, 1H).

EXAMPLE 575(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2-hydroxyethyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred partial solution of Reference Example 11 (318 mg, 0.80mmol) and NaHCO₃ (169 mg, 2.01 mmol) in ethanol (5 ml) under anatmosphere of nitrogen, 2-bromoethanol (151 mg, 1.21 mmol) was addeddropwise. The reaction was then refluxed for 20 hours. Water was added(200 ml) and the reaction extracted with EtOAc and the combined organicphases were washed with sat NaCl and then dried over MgSO₄ andevaporated under reduced pressure. The resulting yellow oil wastriturated with ether to give the title compound as a yellow solid (163mg, 50%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.40 (broad s, 2H), 2.49(Obscured by DMSO,2H), 2.63 (t, 2H), 3.09 (d, 2H), 3.52 (m, 2H), 3.91 (dd, 1H), 4.19 (t,1H), 4.39 (m, 1H), 4.45 (m, 2H), 5.05 (m, 1H), 5.96 (broad s, 1H), 6.37(d, 2H), 7.25-7.38 (m, 2H), 7.47 (dd, 1H), 8.68 (d, 2H). MS: ESP+(M+H)⁺=404.

EXAMPLE 585(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2-acetoxyethyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred solution of Example 57(103 mg, 0.26 mmol) and triethylamine(77.4 mg, 0.77 mmol) in dichloromethane (10 ml) at 0° C. and under anatmosphere of nitrogen, was added dropwise acetyl chloride (60.2 mg,0.77 mmol). The reaction was then allowed to warm to ambient temperatureand stir for 1 hour. Water was added and the organic phase separated,washed with sat NaCl and then dried over MgSO₄ and evaporated underreduced pressure. This yielded the title compound as a clear orangeglass (110 mg, 97%). MS: ESP+ (M+H)⁺=446.

¹H-NMR (300 MHz, DMSO-d6): 2.09 (s, 3H), 2.50 (broad s, 2H), 2.74 (m,4H), 3.20 (broad s, 2H), 3.99 (m, 1H), 4.19-4.29 (m, 3H), 4.53 (m, 2H),5.14 (m, 1H), 6.04 (broad s, 1H), 6.46 (d, 1H), 7.34-7.49 (m, 2H), 7.55(dd, 1H), 8.75 (d, 1H).

EXAMPLE 595(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxan-5-yl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred partial solution of Reference Example 11 (600 mg, 1.52mmol) in MeOH (15 ml), at 0° C. was added dropwise2,2-dimethyl-1,3-dioxan-5-one (218 mg, 1.67 mmol). The reaction wasallowed to warm to ambient temperature and stirred for 40 minutes.Sodium cyanoborohydride (100.4 mg, 1.60 mmol) was then added portionwiseand the reaction stirred for a further 48 hours. The reaction wasquenched with 10% NaOAc and extracted with dichloromethane and thecombined organic phases were dried over MgSO₄ and evaporated underreduced pressure. The reaction was then purified by MPLC (Merck 9385silica, 5% MeOH in dichloromethane). The solvent was removed to yield anorange oil which was triturated with ether to give the title compound asan orange solid (295 mg, 41%). MS: ESP+(M+H)⁺=474.

¹H-NMR (300 MHz, DMSO-d6): δ=1.29 (s, 3H), 1.35 (s, 3H), 2.39 (broad s,2H), 2.58 (m, 1H), 2.74 (m, 2H), 3.22 (d, 2H), 3.78 (m, 2H), 3.92 (m,3H), 4.20 (t, 1H), 4.45 (m, 2H), 5.05 (m, 1H), 5.95 (broad s, 1H), 6.38(d, 1H), 7.29-7.40 (m, 2H), 7.48 (dd, 1H), 8.69 (d, 1H).

EXAMPLE 605(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(1-(hydroxymethyl)-2-hydroxyethyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred solution of Example 59 (203 mg, 0.43 mmol) in THF (15 ml)was added 1N HCl (10 ml). The reaction was allowed to stir at ambienttemperature for 18 hours. The reaction was basified with ammoniasolution until aqueous layer was pH12. The reaction was extracted withEtOAc and the combined organic phases were washed with sat NaCl and thendried over MgSO₄ and evaporated under reduced pressure. The resultingyellow oil was triturated with ether to give the title compound as apale yellow solid (167 mg, 90%). MS: ESP+ (M+H)⁺=434.

¹H-NMR (300 MHz, DMSO-d6): δ=2.39 (broad s, 2H), 2.59 (m, 1H), 2.84 (m,2H), 3.38 (d, 2H), 3.51 (m, 4H), 3.91 (dd, 1H), 4.20 (t, 1H), 4.30(broad s, 2H), 4.48 (m, 2H), 5.08 (m, 1H), 5.96 (broad s, 1H), 6.37 (d,1H), 7.27-7.38 (m, 2H), 7.48 (dd, 1H), 8.69 (d, 1H).

REFERENCE EXAMPLE 333,5-Difluoro-4-(1-methyl-4-hydroxyhexahydropyrid-4-yl)-aniline

To a stirred solution of 3,5-difluoroaniline (7.0 g, 54 mmol) inanhydrous THF (250 ml) under an atmosphere of nitrogen and cooled to−74° C. was added dropwise ^(n)BuLi (1.45M in hexanes, 78.6 ml, 0.114mol) over a period of 10 minutes. The reaction was allowed to stir at−74° C. for 30 minutes. Chlorotrimethylsilane (12.4 g, 0.114 mol), inanhydrous THF (100 ml) was added dropwise over a period of 10 minutes.The solution was allowed to warm to ambient temperature and then stirfor 40 minutes. The reaction was then cooled again to −74° C. and nBuLi(1.45M in hexanes, 43.0 ml, 62.4 mmol) was added dropwise over a periodof 10 minutes. After stirring for a further 3.5 hours at −74° C.,N-methyl-4-piperidone (7.90 g, 70.5 mmol) in anhydrous THF (50 ml) wasadded dropwise over a period of 10 minutes. The reaction was allowed tostir to ambient temperature over the weekend. The reaction was acidifiedwith 10% HCl to pH<1 and extracted with diethyl ether. The aqueous phasewas separated and treated with 40% NaOH to pH 12 then extracted withdiethyl ether and the combined organic phases were washed with sat NaCland then dried over MgSO₄ and evaporated under reduced pressure. Theresulting brown oil was triturated with cyclohexane to give the titlecompound as a pale yellow solid (9.30 g, 71%).

¹H-NMR (300 MHz, DMSO-d6): δ=1.87-2.05 (m, 4H), 2.10 (s, 3H), 2.25-2.42(m, 4H), 4.70 (s, 1H), 5.54 (s, 2H), 6.07 (dd, 2H). MS: ESP+ (M+H)⁺=243;ESP− (M+H)⁺=241.

REFERENCE EXAMPLE 343,5-Difluoro-4-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-aniline

Prepared by the general method of Reference Example 2 using ReferenceExample 33 (9.0 g, 37 mmol) and conc. HCl (35 ml). Yield =8.20 g, 98%.MS: ESP+ (M+H)⁺=225.

¹H-NMR (300 MHz, DMSO-d6): δ=2.25 (s, 5H), 2.50 (partially obscured byDMSO, 2H), 2.93 (m, 2H), 5.60 (broad s, 1H), 5.66 (s, 2H), 6.15 (dd,2H).

REFERENCE EXAMPLE 35N-Benzyloxycarbonyl-3,5-difluoro-4-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)aniline

To a stirred solution of Reference Example 34 (8.20 g, 35.7 mmol) indichloromethane (250 ml) and pyridine (4.00 ml, 49.4 mmol) under anatmosphere of nitrogen at −10° C. was added dropwise benzylchloroformate (7.49 g, 43.9 mmol) in dichloromethane. The reaction wasallowed to warm to ambient temperature and stir for 2 hours. Water andice was added and the organic phase separated, washed with sat NaCl andthen dried over MgSO₄ and evaporated under reduced pressure. Theresulting brown oil was purified by MPLC (Merck 9385 silica, 4-8% MeOHin dichloromethane). The solvent was removed to yield a yellow oil whichwas triturated with cyclohexane to give the title compound as a paleyellow solid (7.60 g, 58%). MS:ESP+ (M+H)⁺=359.

¹H-NMR (300 MHz, DMSO-d6): δ=2.29 (m, 5H), 2.54 (Partially obscured byDMSO, 2H), 2.90 (m, 2H), 5.15 (s, 2H), 5.73 (broad s, 1H), 7.15 (dd,2H), 7.31-7.44 (m, 5H), 10.18 (s, 1H).

REFERENCE EXAMPLE 35A5(R)-Hydroxymethyl-3-(4-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one

To a stirred solution of Reference Example 35 (7.25 g, 20.3 mmol) inanhydrous THF (100 ml) under an atmosphere of nitrogen and cooled to−74° C. was added dropwise ^(n)BuLi (1.45M in hexanes, 14.9 ml, 21.7mmol) over a period of 10 minutes. The reaction was allowed to stir at−74° C. for 30 minutes. R-glycidyl butyrate (3.18 g, 22.1 mmol) wasadded in one portion and the reaction was allowed to warm to ambienttemperature and stir overnight. MeOH (10 ml) was added and the reactionallowed to stir for 10 minutes. Water was added (150 ml) and thereaction extracted with EtOAc and the combined organic phases werewashed with sat NaCl and then dried over MgSO₄ and evaporated underreduced pressure. The resulting oil was triturated with ether to givethe title compound as a pale yellow solid (4.51, 69%).

¹H-NMR (300 MHz, DMSO-d6): δ=2.25 (s, 3H), 2.31 (broad s, 2H), 2.53(partially obscured by DMSO, 2H), 2.98 (m, 2H), 3.55 (m, 1H), 3.67 (m,1H), 3.82 (dd, 1H), 4.06, (t, 1H), 4.71 (m, 1H), 5.21 (m, 1H), 5.78(broad s, 1H), 7.32(dd, 2H). MS: ESP+ (M+H)⁺=325.

There is no Example 61.

EXAMPLE 625(R)-Isoxazol-3-yloxymethyl-3-(4-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Reference Example 35A (1.0 g, 3.10 mmol), 3-hydroxyisoxazole (0.39, 4.59mmol), triphenylphosphine (1.21 g, 4.63 mmol) anddiisopropylazodicarboxylate (1.17 g, 4.64 mmol) in anhydrous THF (60 ml)were reacted using the general method of Example 1. The resultantproduct was purified by MPLC (Merck 9385 silica, 5% MeOH indichloromethane). The solvent was removed to yield a clear orange glass(0.93 g, 77%). MS: ESP+ (M+H)⁺=392.

¹H-NMR (300 MHz, DMSO-d6): δ=2.25 (s, 3H), 2.30 (broad s, 2H), 2.54(Partially obscured by DMSO, 2H), 2.97 (m, 2H), 3.90 (dd, 1H), 4.19 (t,1H), 4.46 (m, 2H), 5.09 (m, 1H), 5.78 (broad s, 1H), 6.37 (d, 1H), 7.31(dd, 2H), 8.68 (d, 1H).

EXAMPLE 635(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-acetamidopropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a solution of Reference Example 11 (500 mg, 1.25 mmol) in anhydrousDMF (25 ml), stirred at room temperature, was added in sequence:N-methylmorpholine(220 μl, 2.0 mmol), N-acetyl-L-isoserine, 220 mg, 1.5mmol), 1-hydroxybenzotriazole (213 mg, 1.5 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (287 mg, 1.5mmol) and stirred for 18 h. The DMF was removed by hi-vac rotaryevaporation and the residue purified by MPLC (Merck 9385 Silica, elutingwith 5%MeOH/CH₂Cl₂) to give the title compound as a white solid (430 mg,70%) upon trituration with diethyl ether. MS: ES⁺. (M+H)⁺=489.

NMR (300 MHz, DMSO-d₆) δ/ppm: 1.78(s, 3H), 2.21(m, 2H), 3.10(m, 1H),3.30(m, 1H), 3.70(m, 2H), 3.92(dd, 1H), 4.08(dd, 2H), 4.21 (m, 2H), 4.43(m, 2H), 5.08 (m, 1H), 5.18 (t, 1H), 6.00 (br s, 1H), 6.38 (d, 1H),7.28-7.41(m, 2H), 7.50 (dd, 1H), 7.92 (m, 1H), 8.65 (d, 1H).

REFERENCE EXAMPLE 365(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-tert-butoxycarbonylamino-3-hydroxy-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

Prepared using the method of Example 63 using the following quantitiesof reagents: Reference Example 11 (1.00 g, 2.5 mmol); DMF (50 ml); :N-methylmorpholine(440 μl, 4.0 mmol); N-BOC-L-serine(616 mg, 3.0 mmol);1-hydroxybenzotriazole(425 mg, 3.0 mmol);1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575 mg, 3.0mmol). Yielding the title compound as a white foam (1.32 g, 96%).

NMR (300 MHz, DMSO-d₆) δ/ppm: (300 MHz, DMSO-d₆) δ/ppm:

1.37 (s, 9H), 2.40 (m, partly obscured, 2H), 3.46 (m,1H), 3.57 (m, 1H),3.70 (m, 2H), 3.93 (dd, 1H), 4.06 (s, 1H), 4.20 (m, 2H), 4.46 (m, 3H),4.81 (t, 1H), 5.08 (m, 1H), 6.02 (br s, 1H), 6.38 (d, 1H), 6.86 (dd,1H), 7.35 (m, 2H), 7.50 (d, 1H), 8.69 (d, 1H). MS: ES⁺. (M+H)⁺=547.

REFERENCE EXAMPLE 375(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-amino-3-hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

TFA (2.0 ml) was added to Reference Example 36 (250 mg, 0.46 mmol) withsome gas evolution and stirred at room temperature for 5 minutes,producing a yellow solution. The excess TFA was removed by rotaryevaporation and the title compound (230 mg, 89%) obtained as a paleyellow solid upon trituration with diethyl ether. MS: ES⁺. (M+H)⁺=447.

EXAMPLE 645(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-acetamido-3-hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

To a stirred solution of Reference Example 37 (168 mg, 0.3 mmol) andsodium bicarbonate(totalling 202 mg, 2.4 mmol) in acetone/water (10 ml,1:1), cooled at 0° C., under N₂ was added drop-wise, acetyl chloride(totalling 70.6 mg, 0.90 mmol) in acetone (1.0 ml) and stirred for 5hours. The acetone was removed by rotary evaporation, water and 1N. HClsolution added to pH=5 and extracted with CH₂Cl₂ (3×), the organicphases were separated, and the title compound obtained as a white solid(30 mg, 20%) following MPLC (Merck 9385 silica, eluting with10%MeOH/CH₂Cl₂) and trituration with diethyl ether. MS: (M+H)⁺=489.

NMR (400 MHz, DMSO-d₆) δ/ppm: (300 MHz, DMSO-d₆) δ/ppm: 1.84 (s, 3H),2.47 (d, partially obscured, 2H), 3.46 (m, 1H), 3.62 (m, 1H), 3.73 (m,2H), 3.96 (t, 1H), 4.10-4.30 (m, 3H), 4.50 (m, 2H), 4.88 (m, 2H), 5.11(m, 1H), 6.03 (br s, 1H), 6.40 (d, 1H), 7.35 (dd, 1H), 7.41 (m, 1H),7.52 (dd, 1H), 8.07 (t, 1H), 8.70 (d, 1H).

EXAMPLE 653-(4-(3-Hydroxy-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yl-oxymethyl)oxazolidin-2-one

3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (230 mg, 0.5 mmol) was dissolved intetrahydrofuran (10 ml), and cooled under nitrogen to 0°. A solution oftetra-n-butylammonium fluoride (1 M, 1 ml, 1 mmol) was added and themixture allowed to come to ambient temperature. Water (2 ml) was added,and the mixture evaporated to dryness. The residue was purified bychromatography on a 10 g silica Mega Bond Elut(D column, eluting with agradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane.Relevant fractions were combined and evaporated, then redissolved inEtOAc and the desired product (96 mg) precipitated by addition ofisohexane.

MS (ESP): 350 (MH⁺) for C₁₆H₁₆FN₃O₅

NMR (DMSO-d₆) δ: 3.52 (t, 2H); 3.83 (dd, 1H); 4.09 (overlapping m, 3H);4.45 (m, 2H); 4.51 (quintet, 1H); 5.00 (m, 1H); 5.53 (d, 1H); 6.37 (d,1H); 6.56 (t, 1H); 7.11 (dd, 1H); 7.37 (dd, 1H); 8.66 (d, 1H).

The intermediate for this compound was prepared as follows:

3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yl-oxymethyl)oxazolidin-2-one

3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one(WO 96/13502; 2.47 g, 6.25 mmol), 3-hydroxyisoxazole (580 mg, 6.86mmol), and tributylphosphine (1.58 g, 7.8 mmol) were dissolved bystirring in dry tetrahydrofuran (100 ml) under nitrogen. The mixture wascooled in an ice-bath, and 1,1′-(azodicarbonyl)dipiperidine (1.96 g, 7.8mmol) added dropwise over 10 minutes. The solution was stirred 18 hours,allowing the temperature to rise to ambient. Reduced azo compound wasfiltered off, and the solution evaporated to dryness and the residuetriturated with ether. The residue was purified by chromatography on asilica flash column, eluting with a gradient from 50 to 75% EtOAc inisohexane. Relevant fractions were combined and evaporated to theproduct as an oil (1.31 g).

NMR (DMSO-d₆) δ: 0.00 (s, 6H); 0.79 (s, 9H); 3.47 (t, 2H); 3.77 (dd,1H); 4.07 (t, 1H); 4.11 (t, 2H); 4.39 (m, 2H); 4.65 (quintet, 1H); 4.95(m, 1H); 6.30 (d, 1H); 6.53 (t, 1H); 7.06 (dd, 1H); 7.33 (dd, 1H); 8.61(d, 1H).

EXAMPLE 663-(4-(3-Oxo-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-4-(3-Hydroxy-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(349 mg, 1 mmol) was dissolved in dry DMSO(5 ml) under nitrogen, andtreated with pyridine sulfur trioxide complex (502 mg, 3.15 mmol) in dryDMSO(5 ml) over 10 minutes. The solution was stirred 3 hours, pouredinto water (100 ml), and extracted with EtOAc (3×50 ml). The organicextracts were washed with water (3×50 ml), saturated brine (50 ml), anddried (magnesium sulfate). The residue was purified by chromatography ona 10 g silica Mega Bond Elut® column, eluting with a gradient increasingin polarity from 0 to 5% MeOH in dichloromethane. Relevant fractionswere combined, evaporated, and the residue triturated with diethyl etherto give the desired product (227 mg).

MS (ESP): 348 (MH⁺) for C₁₆H₁₄FN₃O₅; 380 (MH⁺+MeOH) for C₁₇H₁₈FN₃O₆. NMR(DMSO-d₆) δ: 3.89 (dd, 1H); 4.16 (t, 1H); 4.47 (m, 2H), 4.76 (s, 4H);5.04 (m, 1H); 6.38 (d, 1H); 6.77 (d, 1H); 7.21 (dd, 1H); 7.49 (dd, 1H);8.67 (d, H1).

EXAMPLE 673-(4-(4-t-Butoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-t-Butoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one(WO 93/23384; 10 g, 25.3 mmol), 3-hydroxyisoxazole (2.58 g, 30 mmol),and triphenylphosphine (9.95 g, 37.8 mmol) were dissolved in anhydroustetrahydrofuran (300 ml), and cooled under nitrogen to 4°.Diisopropylazodicarboxylate (6.04 g, 30 mmol) was added dropwise over 10minutes, and stirring was continued at the same temperature for 2 hours.The mixture was evaporated to dryness, and the residue purified by flashchromatography on silica, eluting with 50% EtOAc in isohexane. Relevantfractions were combined and evaporated to give the desired product (10.2g).

MS (ESP): 463 (MH⁺) for C₂₂H₂₇FN₄O₆ NMR (DMSO-d₆) δ: 1.39 (s, 9H); 2.91(t, 4H); 3.45 (t, 4H); 3.87 (dd, 1H); 4.14 (t, 1H); 4.44 (m, 2H); 5.03(m, 1H); 6.35 (d, 1H); 7.06 (t, 1H); 7.18 (dd, 1H); 7.36 (dd, 1H); 8.66(d, 1H).

EXAMPLE 683-(4-(Piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-oneDihydrochloride

3-(4-(4-t-Butoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one(10.24 g, 22 mmol) was suspended in ethanol (150 ml), and a solution ofhydrogen chloride in ethanol (5M, 75 ml) added at 0°. A completesolution occurred, and the solution was left to stir 18 hours at ambienttemperature, as product precipitated. After dilution with anhydrousdiethyl ether (200 ml), the product (8.91 g) was filtered off.

Microanalysis: Found: C, 46.9, H, 4.8, N, 12.2%; C₁₇H₁₉FN₄O₄.2HClrequires C, 46.9, H, 4.6, N, 12.9%. MS (ESP): 363 (MH⁺) for C₁₇H₁₉FN₄O₄NMR (DMSO-d₆) δ: 3.19 (s, 8H); 3.87 (dd, 1H); 4.16 (t, 1H); 4.45 (m,2H); 5.03 (m, 1H); 6.36 (d, 1H); 7.11 (t, 1H); 7.22 (dd, 1H); 7.51 (dd,1H); 8.68 (d, 1H); 9.47 (br, 2H).

EXAMPLE 693-(4-(4-(2(R),3-Dihydroxypropanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

A solution of 2,2-dimethyl-1,3-dioxolane-4(R)-carboxylic acid (162 mg,1.1 mmol) in dichloromethane (20 ml) under nitrogen was cooled withstirring to 4°, and treated successively with dicyclohexylcarbodiimide(227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (147 mg, 1.1 mmol), thenstirred at the same temperature for 1 hour. N,N-Diisopropylethylamine(129 mg, 1 mmol) was added, followed by3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (399 mg, 0.92 mmol). The mixture was stirred for 2hours, allowing the temperature to rise to ambient. Solid was filteredoff, and the organic solution washed with water (2×20 ml), dried overmagnesium sulfate and evaporated to dryness. The residue was purified bychromatography on a 10 g silica Mega Bond Elut® column, eluting with agradient increasing in polarity from 0 to 10% MeOH in dichloromethane.Relevant fractions were combined and evaporated to give the desiredproduct (82 mg).

MS (ESP): 451 (MH⁺) for C₂₀H₂₃FN₄O₇ NMR (DMSO-d₆) δ: 2.93 (br m, 4H);3.49 (m, 2H); 3.66 (br m, 4H); 3.88 (dd, 1H); 4.14 (t, 1H); 4.34 (m,1H); 4.43 (m, 2H); 4.67 (m, 1H); 4.92 (d, 1H); 5.04 (m, 1H); 6.36 (d,1H); 7.06 (t, 1H); 7.20 (dd, 1H); 7.51 (dd, 1H); 8.67 (d, 1H).

EXAMPLE 703-(4-(4-(2(S),3-Dihydroxypropanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using the same procedure and scale as Example 69, but starting from2,2-dimethyl-1,3-dioxolane-4(S)-carboxylic acid, the title compound (75mg) was obtained,

MS (ESP): 451 (MH⁺) for C₂₀H₂₃FN₄O₇ NMR (DMSO-d₆) δ: 2.93 (br m, 4H);3.45 (m, 1H); 3.53 (m, 1H); 3.65 (br m, 4H); 3.87 (dd, 1H); 4.16 (t,1H); 4.34 (dd, 1H); 4.45 (m, 2H); 4.67 (t, 1H); 4.92 (d, 1H); 5.04 (m,1H); 6.37 (d, 1H); 7.07 (t, 1H); 7.20 (dd, 1H); 7.51 (dd, 1H); 8.67 (d,1H).

EXAMPLE 713-(4-(4-(2-(2-Methoxyethoxy)ethoxy)acetylpiperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

To a solution of3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-onedihydrochloride (399 mg, 0.92 mmol) in pyridine (10 ml) was addedtriethylamine (0.31 ml, 2.2 mmol) and2-(2-(2-methoxyethoxy)ethoxy)acetyl chloride (197 mg, 1 mmol). Themixture was stirred for 18 hours, evaporated to dryness, the residuedissolved in dichloromethane, and purified by chromatography on a 10 gsilica Mega Bond Elut® column, eluting with a gradient increasing inpolarity from 0 to 10% MeOH in dichloromethane. Relevant fractions werecombined and evaporated to give the desired product (95 mg).

MS (ESP): 523 (MH⁺) for C₂₄H₃₁FN₄O₈ NMR (DMSO-d₆) δ: 2.93 (br m, 4H);3.21 (s, 3H); 3.41 (t, 2H); 3.47 (t, 2H); 3.54 (overlapping m, 8H); 3.87(dd, 1H); 4.14 (t, 1H); 4.16 (s, 2H); 4.45 (m, 2H); 5.03 (m, 1H); 6.36(d, 1H); 7.06 (t, 1H); 7.20 (dd, 1H); 7.51 (dd, 1H), 8.67 (d, 1H).

EXAMPLE 723-(4-(4-(3-Hydroxy-2-hydroxymethylpropanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-(2-Phenyl-1,3-dioxan-5-ylcarbonyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(450 mg, 0.82 mmol) was dissolved in a mixture of acetic acid and water(4:1, 10 ml) and stirred at ambient temperature for 18 hours. Afterevaporation to dryness, the residue was azeotroped with toluene (15 ml),and the residual gum purified by chromatography on a 20 g silica MegaBond Elut® column, eluting with a gradient increasing in polarity from 5to 10% MeOH in dichloromethane. Relevant fractions were combined andevaporated to give the desired product (237 mg).

MS (ESP): 465 (MH⁺) for C₂₁H₂₅FN₄O₇ NMR (DMSO-d₆) δ: 2.94 (br d, 4H);3.05 (quintet, 1H); 3.47 (m, 4H); 3.65 (br d, 4H); 3.87 (dd, 1H); 4.15(t, 1H); 4.46 (m, 2H); 4.56 (t, 2H); 5.03 (m, 1H); 6.34 (d, 1H); 7.06(t, 1H); 7.19 (dd, 1H); 7.50 (dd, 1H); 8.67 (d, 1H),

The intermediate for this compound was prepared as follows:

3-(4-(4-(2-Phenyl-1,3-dioxan-5-ylcarbonyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

To a stirred solution of 2-phenyl-1,3-dioxan-5-ylcarboxylic acid (478mg, 2.3 mmol) and N-hydroxysuccinimide (291 mg, 2.5 mmol) in anhydrousdichloromethane (25 ml) at 0° was added dicyclohexylcarbodiimide (522mg, 2.5 mmol). After sitting 1 hour at 0°, N,N-diisopropylethylamine(623 mg, 4.8 mmol) was added, followed by3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (1 g, 2.3 mmol) in portions over 5 minutes. Thetemperature was allowed to rise to ambient, and stirring continued for 3hours. Solid was filtered off, washed with dichloromethane (2×20 ml),and the combined organics evaporated to dryness. The residue waspurified by chromatography on a 20 g silica Mega Bond Elut® column,eluting with a gradient increasing in polarity from 0 to 10% MeOH indichloromethane. Relevant fractions were combined and evaporated to givethe required product (890 mg) as a mixture of cis and trans isomers.

MS (ESP): 553 (MH⁺) for C₂₈H₂₉FN₄O₇ NMR (DMSO-d₆) δ: 2.93 (br d, 4H);3.58 (br, 4H); 3.87 (dd, 1H); 3.96-4.30 (overlapping m, 6H); 4.45 (m,2H); 5.03 (m, 1H); 5.53 (2×s, 1H); 6.36 (d, 1H); 7.06 (t, 1H); 7.21 (dd,1H); 7.34 (m, 5H): 7.51 (dd, 1H): 8.66 (d, 1H).

EXAMPLE 733-(4-(4-Acetoxyacetylpiperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yl-oxymethyl)oxazolidin-2-one

3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (1.29 g, 3 mmol) was suspended in dichloromethane (25ml) under nitrogen at ambient temperature. Triethylamine (1.06 g, 10.5mmol) was added, to give a solution after 15 minutes. The mixture wascooled to 4°, and acetoxyacetyl chloride (410 mg, 3 mmol) was addeddropwise. The mixture was stirred for 18 hours at ambient temperature,washed with water (2×20 ml), saturated brine (20 ml), and dried(magnesium sulfate). The residue was purified by chromatography on a 20g silica Mega Bond Elut® column, eluting with a gradient increasing inpolarity from 0 to 5% MeOH in dichloromethane. Relevant fractions werecombined and evaporated to give the desired product (1.16 g).

MS (ESP): 463 (MH⁺) for C₂₁H₂₃FN₄O₇ NMR (DMSO-d₆) δ: 2.07 (s, 3H); 2.94(br, 4H); 3.53 (br d, 4H); 3.87 (dd, 1H); 4.16 (t, 1H); 4.45 (m, 2H);4.78 (s, 2H); 5.03 (m, 1H); 6.36 (d, 1H); 7.08 (t, 1H); 7.21 (dd, 1H);7.48 (dd, 1H); 8.66 (d, 1H).

EXAMPLE 743-(4-(4-Hydroxyacetylpiperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-(Acetoxyacetyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl-oxazolidin-2-one(0.93 g, 2 mmol) and potassium carbonate (417 mg, 3 mmol) were stirredat ambient temperature under nitrogen in MeOH (20 ml) for 4 hours. Themixture was evaporated to dryness, dissolved in dichloromethane (80 ml),washed with water (2×30 ml), saturated brine (30 ml), and dried(magnesium sulfate). Filtration and evaporation gave the desired product(0.59 g).

MS (ESP): 421 (MH⁺) for C₁₉H₂₁FN₄O₆; NMR (DMSO-d₆) δ: 2.93 (br, 4H);3.48 (br s, 2H); 3.60 (br s, 2H); 3.86 (dd, 1H); 4.11 (d, 2H); 4.15 (t,1H); 4.45 (m, 2H); 4.58 (d, 1H); 5.04 (m, 1H); 6.37 (d, 1H); 7.06 (t,1H); 7.21 (dd, 1H); 7.51 (dd, 1H); 8.66 (d, 1H).

EXAMPLE 753-(4-(4-Acetylpiperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxy-methyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example73, starting from3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (0.59 g, 1.35 mmol) and acetyl chloride. Purification bychromatography, eluting with a gradient increasing in polarity from 0 to2.5% MeOH in dichloromethane gave the desired product (142 mg).

MS (ESP): 405 (MH⁺) for C₁₉H₂₁FN₄O₅; NMR (DMSO-d₆) δ: 2.02 (s, 3H): 2.93(br d, 4H); 3.55 (br, 4H); 3.87 (dd, 1H); 4.16 (t, 1H); 4.45 (m, 2H);5.04 (m, 1H); 6.36 (d, 1H); 7.06 (t, 1H); 7.20 (dd, 1H); 7.51 (dd, 1H);8.66 (d, 1H).

EXAMPLE 763-(4-(4-((3R)-3-Hydroxy-4-trimethylammoniobutanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onechloride

3-(4-(4-((3R)-3-Acetoxy-4-trimethylarnmoniobutanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onechloride (200 mg, 0.33 mmol) and potassium carbonate (67 mg, 0.49 mmol)were stirred at ambient temperature under nitrogen in MeOH (20 ml) for 5hours. The mixture was evaporated to dryness, the solid triturated withwater, filtered and washed with water (20 ml) to give the desiredproduct (137 mg). MS (ESP): 506 (M⁺) for C₂₄H₃₃FN₅O₆;

NMR(DMSO-d₆) δ: 2.51 (dd, 1H); 2.65 (dd, 11H); 2.93 (br d, 4H); 3.14 (s,9H); 3.61 (br s, 4H); 3.87 (dd, 1H); 4.17 (t, 1H); 4.47 (m, 3H); 5.05(m, 1H); 5.74 (br, 1H); 6.38 (d, 1H); 7.07 (t, 1H); 7.23 (dd, 1H); 7.52(dd, 1H); 8.69 (d, 1H).

The intermediate for this compound was prepared as follows:

3-(4-(4-((3R)-3-Acetoxy-4-trimethylammoniobutanoyl)piperazin-1-yl)-3-fluoronhenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onechloride

(3R)-3-Acetoxy-4-trimethylamrnoniobutanoic acid (527 mg, 2.2 mmol, seeJ. Org. Chem., 1967, 32, 3989) was stirred in thionyl chloride (3 ml) atambient temperature for 3 hours, giving a solution. Excess thionylchloride was evaporated, and the residue azeotroped with toluene, beforedissolving in anhydrous dichloromethane (10 ml). This solution was addeddropwise to a solution of3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (0.87 g, 2 mmol) and triethylamine (404 mg, 4 mmol) inanhydrous dichloromethane (10 ml) at 4°. The mixture was stirred for 18hours at ambient temperature, then evaporated to dryness. The residuewas dissolved in brine (20 ml) and purified by chromatography on anHP20SS resin column, eluting with a gradient increasing in polarity from0 to 10% in acetonitrile in water. Relevant fractions were combined,evaporated to dryness, dissolved in de-ionised water (50 ml), andfreeze-dried to give the required product (0.39 g). MS (ESP): 548 (M⁺)for C₂₆H₃₅FN₅O₇;

NMR (DMSO-d₆) δ: 2.05 (s, 3H); 2.82 (d, 2H); 2.94 (br m, 4H); 3.12 (s,9H); 3.55 (br m, 4H); 3.58-3.78 (overlapping m, 2H); 3.87 (dd, 1H); 4.17(t, 1H); 4.46 (m, 2H); 5.04 (m, 1H); 5.49 (m, 1H); 6.38 (d, 1H); 7.06(t, 1H); 7.21 (dd, 1H); 7.51 (dd, 1H); 8.68 (d, 1H).

EXAMPLE 773-(4-(4-Methoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (866 mg, 2 mmol) was suspended in dichloromethane (40ml) under nitrogen at ambient temperature. Triethylamine (707 mg, 7mmol) was added, followed by methyl chloroforrnate (190 mg, 2 mmol). Themixture was stirred for 2 hours at ambient temperature, washed withwater (2×50 ml), saturated brine (50 ml), and dried (magnesium sulfate).After filtration and evaporation, the residue was triturated withdiethyl ether to give the desired product (689 mg).

MS (ESP): 421 (MH⁺) for C₁₉H₂₁FN₄O₆; NMR (DMSO-d₆) δ: 2.93 (t, 4H); 3.52(t d, 4H); 3.62 (s, 3H); 3.89 (dd, 1H); 4.16 (t, 1H); 4.46 (m, 2H); 5.04(m, 1H); 6.37 (d, 1H); 7.08 (t, 1H); 7.20 (dd, 1H); 7.52 (dd, 1H); 8.67(d, 1H).

EXAMPLE 783-(4-(4-(3-(4-Imidazolyl)acryloyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yioxymethyl)oxazolidin-2-one

3-(4-Imidazolyl)acrylic acid (690 mg, 5 mmol) was suspended in anhydrousdichloromethane (5 ml) under nitrogen, and thionyl chloride (10 ml) andone drop of DMF added. The mixture was stirred at ambient temperaturefor 18 hours, excess thionyl chloride was evaporated, and the residueazeotroped with dichloromethane (2×50 ml). The acid chloride wassuspended in dichloromethane (30 ml), cooled to 4°, and a solution of3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (866 mg, 2 mmol) and triethylamine (2.02 g, 20 mmol) inanhydrous dichloromethane (25 ml) added dropwise. The mixture wasstirred for 18 hours at ambient temperature, and insoluble materialfiltered. The organic layer was treated with water (50 ml), furtherinsoluble material removed, then washed with brine and dried overmagnesium sulfate. After evaporation to dryness, the residue wasdissolved in ethanol (5 ml) and treated with an excess of ethanolsaturated with hydrogen chloride, to precipitate the desired product asa hydrochloride salt (122 mg).

Microanalysis: Found: C, 48.2, H, 5.0, N, 14.4%; C₂₃H₂₃FN₆O₅.2HCl.H₂Orequires C, 48.1, H, 4.7,N, 14.4%. MS (ESP): 483 (MH⁺) for C₂₃H₂₃FN₆O₅;NMR (DMSO-d₆) δ: 3.01 (br, 4H); 3.86 (complex, overlapped by H₂O, ˜5H);4.16 (t, 1H); 4.45 (m, 2H); 5.04 (m, 1H); 6.36 (d, 1H); 7.08 (t, 1H);7.21 (dd, 1H); 42 (d, 1H); 7.51 (dd, 1H); 7.71 (d, 1H); 7.97 (s, 1H);8.66 (d, 1H); 9.20 (s, 1H).

EXAMPLE 793-(4-(4-(4-Imidazolylacetyl)-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using the procedure of Example 78, but starting with 4-imidazolylaceticacid hydrochloride salt (810 mg, 5 mmol), the acid chloride was preparedand reacted with the piperazine. After 18 hours reaction, the mixturewas diluted with saturated sodium carbonate solution (20 ml). Theorganic layer was washed with water (2×50 ml), then brine (30 ml) anddried over magnesium sulfate. The residue was purified by chromatographyon a 40 g silica Mega Bond Elut® column, eluting with 10% MeOH indichloromethane. Relevant fractions were combined and evaporated. theresidue dissolved in ethanol (5 ml) and treated with an excess ofethanol saturated with hydrogen chloride, then excess of diethyl etherto precipitate the desired product as a hydrochloride salt (124 mg).

Microanalysis: Found: C, 47.3, H, 5.1, N, 14.8%; C₂₂H₂₃FN₆O₅.2HCl.H₂Orequires C, 47.0, H, 4.8, N, 15.0%. MS (ESP): 471 (MH⁺) for C₂₂H₂₃FN₆O₅;NMR (DMSO-d₆) δ: 2.95 (br m, 2H); 3.03 (br m, 2H); 3.63 (br m, 2H); 3.68(br m, 2H); 3.95 (s+m, overlapped by H₂O, ˜3H); 4.17 (t, 1H); 4.45 (m,2H); 5.04 (m, 1H); 6.36 (d, 1H); 7.08 (t, 1H); 7.22 (dd, 1H); 7.44 (s,1H); 7.52 (dd, 1H); 8.67 (d, 1H); 9.01 (s, 1H); 14.38 (br 2H).

EXAMPLE 803-(4-(4-(3-(4-Imidazolyl)propanoyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-(3-(1-Triphenylmethyl-4-imidazolyl)propanoyl)-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(460 mg, 0.63 mmol), was dissolved in a mixture of ethanol (20 ml) andMeOH (10 ml), cooled to 0° and treated with a solution of hydrogenchloride in ethanol (3.8 M, 5 ml). After stirring 48 hours at ambienttemperature, the pH was adjusted to 8 with triethylamine, and themixture evaporated to dryness. The residue was purified bychromatography on a 10 g silica Mega Bond Elut® column, eluting with agradient from 0 to 20% MeOH in dichloromethane. Relevant fractions werecombined and evaporated to give the desired product (60 mg). MS (ESP):485 (MH⁺) for C₂₃H₂₅FN₆O₅;

NMR (DMSO-d6) δ: 2.59 (t, 2H); 2.74 (t, 2H); 2.92 (br, 4H); 3.60 (br,4H); 3.90 (dd, 1H); 4.16 (t, 1H); 4.46 (m, 2H); 5.06 (m, 1H); 6.38 (d,1H); 6.76 (s, 1H); 7.06 (t, 1H); 7.22 (dd, 1H); 7.59 (s, 1H); 7.63 (dd1H); 8.67 (d, 1H); 11.72 (br 1H).

The intermediates for this compound were prepared as follows:

3-(4-(4-(3-(1-Triphenylmethyl-4-imidazolyl)propanoyl)-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(1-Triphenylmethyl-4-imidazolyl)propionic acid (420 mg, 1.1 mmol) wassuspended in dichloromethane (10 ml) under nitrogen, and treatedsuccessively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and1-hydroxybenzotriazole (149 mg, 1.1 mmol), then stirred at ambienttemperature for 30 minutes. To it was added a solution of3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg,2 mmol) in dichloromethane (5 ml). The mixture was stirred for 18 hoursat the same temperature, solid filtered off, and the organic phasepurified by chromatography on a 20 g silica Mega Bond Elut® column,eluting with a gradient increasing in polarity from 0 to 15% MeOH indichloromethane. Relevant fractions were combined and evaporated to givethe desired product (460 mg).

MS (ESP): 727 (MH⁺) for C₄₂H₃₉FN₆O₅; NMR (DMSO-d₆) δ: 2.61 (t, 2H); 2.70(t, 2H); 2.87 (br, 4H); 3.54 (br, 4H); 3.88 (dd, 1H); 4.17 (t, 1H); 4.45(m, 2H); 5.06 (m, 1H); 6.37 (d, 1H); 6.66 (d, 1H); 7.03 (t, 1H); 7.06(d, 6H); 7.21 (dd, 1H); 7.25 (s, 1H); 7.36 (m, 9H); 7.52 (dd, 1H); 8.67(d, 1H).

3-(1-Triphenylmethyl-4-imidazolyl)propionic Acid

3-(4-Imidazolyl)propionic acid (1.0 g, 7.1 mmol) was suspended in amixture of dichloromethane (5 ml) and acetonitrile (25 ml).Trimethylsilyl chloride (781 mg, 7.2 nmmol) was added and the mixturerefluxed for 4 hours. Triethylamine (1 ml) was added, and refluxingcontinued for 15 minutes. Cooled, triethylamine (1 ml) added followed bychlorotriphenylmethane (1.99 g, 7.1 mmol) in dichloromethane (10 ml),and the mixture stirred at ambient temperature for 2 hours. MeOH (20 ml)was added, the mixture stirred for 30 minutes, then evaporated todryness. Water (50 ml) was added to the residue, and the pH adjusted to8-8.5 with triethylamine. The precipitate was filtered off, washed withdiethyl ether, and dried to give the desired product (2.25 g). MS (ESP):383 (MH⁺) for C₂₅H₂₂N₂O₂;

NMR (DMSO-d₆) δ: 2.48 (t, 2H); 2.77 (t, 2H); 6.65 (s, 1H); 7.08 (d, 6H);7.29 (s, 1H); 7.36 (m, 9H); 12.10 (br, 1H).

EXAMPLE 813-(4-(4-Methanesulfonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (433 mg, 1 mmol) in pyridine (15 ml) and dichloromethane(15 ml) was treated with triethylarnine (353 mg, 3.5 mmol) and stirredfor 30 minutes at ambient temperature. Methanesulfonyl chloride (138 mg,1.2 mmol) was added and the mixture stirred for 18 hours. The mixturewas diluted with dichloromethane (50 ml), washed with water (2×25 ml),saturated brine (25 ml), and dried (magnesium sulfate). Afterevaporation to dryness and azeotroping with toluene (10 ml), the residuewas triturated with diethyl ether to give the desired product (365 mg).

MS (ESP): 441 (MH⁺) for C₁₈H₂₁FN₄O₆S; NMR (DMSO-d₆) δ: 2.91 (s, 3H);3.05 (br m, 4H); 3.26 (br m, 4H); 3.87 (dd, 1H); 4.15 (t, 1H); 4.42 (dd,1H); 4.48 (dd, 1H); 5.05 (m, 1H); 6.36 (d, 1H); 7.10 (t, 1H); 7.21 (dd,1H); 7.48 (dd, 1H); 8.66 (d, 1H).

EXAMPLE 823-(4-(4-Chloroacetyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Chloroacetyl chloride (114 mg, 1 mmol) was added to a stirred solutionof3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (435 mg, 1 mmol) and triethylamine (302 mg, 3 mmol) indichloromethane (10 ml) at ambient temperature. After 10 minutes thereaction was purified by direct chromatography on a 10 g silica MegaBond Elut® column, eluting with dichloromethane. Relevant fractions werecombined and evaporated to give the desired product (390 mg). MS (ESP):439 (MH⁺) for C₁₉H₂₀ClFN₄O₅;

NMR (DMSO-d₆) δ: 2.93 (br m, 2H); 2.99 (br m, 2H); 3.59 (br m, 4H); 3.87(dd, 1H); 4.16 (t, 1H); 4.40 (s, 2H); 4.46 (m, 2H); 5.04 (m, 1H); 6.36(d, 1H); 7.07 (t, 1H); 7.21 (dd, 1H); 7.51 (dd, 1H); 8.66 (d, 1H).

EXAMPLE 833-(4-(4-Morpholinoacetyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

The preparation of Example 82 was repeated up to the stage of formingthe chloroacetylamide. The mixture was then cooled to 0° and treatedwith morpholine (0.262 mg, 3 mmol), then stirred 48 hours allowing thetemperature to rise to ambient. The reaction was evaporated to dryness,and purified by chromatography on a 10 g silica Mega Bond Elut® column,eluting with a gradient from 0 to 10% MeOH in dichloromethane. Relevantfractions were combined and evaporated to give the desired product aftertrituration with diethyl ether (420 mg).

MS (ESP): 490 (MH⁺) for C₂₃H₂₈FN₅O₆; NMR (CDCl₃) δ: 2.52 (br m, 4H);3.03 (m, 4H); 3.23 (s, 2H); 3.71 (m, 4H); 3.77 (m, 4H); 3.93 (dd, 1H);4.14 (t, 1H); 4.50 (dd, 1H); 4.57 (dd, 1H); 5.01 (m, 1H); 6.00 (d, 1H);6.92 (t, 1H); 7.26 (dd, 1H); 7.47 (dd, 1H); 8.16 (d, 1H).

EXAMPLE 843-(4-(4-((2S,4R)-1-Acetyl-4-hydroxy-2-pyrrolidinylcarbonyl)-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

A suspension of (2S,4R)-1-acetyl-4-hydroxy-2-pyrrolidinecarboxylic acid(173 mg, 1 mmol) in dichloromethane (10 ml) and DMF (2 ml) undernitrogen was treated successively with dicyclohexylcarbodiimide (227 mg,1.1 mmol) and 1-hydroxybenzotriazole (149 mg, 1.1 mmol), then stirred atambient temperature for 1 hour. A solution of3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg,2 mmol) in dichloromethane (5 ml) was added, and the mixture stirred for18 hours. Solid was filtered off, the organic solution evaporated todryness, and the residue purified by chromatography on a 10 g silicaMega Bond Elut® column, eluting with a gradient increasing in polarityfrom 0 to 15% MeOH in dichloromethane. Relevant fractions were combinedand evaporated to give the desired product after trituration withdiethyl ether (210 mg).

MS (ESP): 518 (MH⁺) for C₂₄H₂₈FN₅O₇; NMR (CDCl₃) δ: 2.08 (s, 3H); 2.16(m, 3H); 2.45 (m, 1H); 3.05 (m, 3H); 3.19 (m, 1H); 3.62 (overlapping m,2H); 3.91 (dd overlapping m, 4H); 4.13 (t, 1H); 4.49 (dd, 1H); 4.56 (dd,1H); 4.66 (m, 1H); 5.01 (overlapping m, 2H); 5.99 (d, 1H); 6.92 (t, 1H);7.27 (dd, 1H); 7.48 (dd, 1H); 8.15 (d, 1H).

EXAMPLE 853-(4-(4-((2S,4R)-1-Methyl-4-hydroxy-2-nyrrolidinylcarbonyl)-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

A solution of3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onedihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg,2 mmol) in DMF (2 ml) was added to a stirred solution of (2S,4R)-1-methyl-4-hydroxy-2-pyrrolidinecarboxylic acid (145 mg, 1 mmol ;see Angewandte Chemie, 1995, 9, 1095) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (380 mg, 1 mmol) in DMF (5 ml) under nitrogen atambient temperature. N,N-Diisopropylethylamine (387 mg, 3 mmol) wasadded, and the mixture stirred at ambient temperature for 18 hours.After evaporation to dryness, the residue was partitioned between water(5 ml) and dichloromethane (10 ml). The separated organic laver wasevaporated, and the residue purified by chromatography on a 10 g silicaMega Bond Elut® column, eluting with a gradient increasing in polarityfrom 0 to 10% MeOH in dichloromethane. Relevant fractions were combinedand evaporated to give the desired product (256 mg). MS (ESP): 490 (MH⁺)for C₂₃H₂₈FN₅O₆.

NMR (CDCl₃) δ: 1.96 (m, 1H); 2.07 (m, 1H); 2.36 (m, 1H); 2.38 (s, 3H);3.02 (m, 4H); 3.33 (dd, 1H); 3.71 (overlapping m, 5H); 3.89 (dd, 1H);4.18 (t, 1H); 4.30 (m, 1H); 4.46 (m, 1H); 4.53 (dd, 1H): 4.59 (m, 1H);5.03 (m, 1H); 6.28 (d, 1H); 7.08 (t, 1H); 7.20 (dd, 1H); 7.46 (dd, 1H);8.57 (d, 1H).

EXAMPLE 863-(4-((3R)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyloxazolidin-2-one

3-(4-((3R)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(108 mg, 0.23 mmol) was dissolved in dichloromethane (7 ml) undernitrogen and treated with TFA (3 ml) at ambient temperature. The mixturewas stirred 48 hours, evaporated to dryness, and azeotroped with toluene(2×10 ml). The resulting gum was taken up in ethanol (5 ml), and asolution of hydrogen chloride in ethanol (3.8M, 2 ml). Excess diethylether was added to precipitate the title compound as its hydrochloride(80 mg).

MS (ESP): 363 (MH⁺) for C₁₇H₁₉FN₄O₄; NMR (DMSO-d₆) δ: 1.99 (m, 1H); 2.23(m, 1H); 3.25 (m, 1H); 3.41 (m, 1H); 3.52 (m, 2H); 3.84 (dd, 1H); 4.14(t, 1H); 4.42 (m overlapping H₂O, ˜3H); 5.02 (m, 1H); 6.37 (d, 1H); 6.79(t, 1H); 7.15 (dd, 1H); 7.44 (dd, 1H); 8.34 (br, 2H); 8.68 (d, 1H).

The intermediates for this compound were prepared as follows

3-Fluoro-4-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)nitrobenzene

3,4-Difluoronitrobenzene (16.03 g, 0.101 M) was dissolved inacetonitrile (300 ml), and treated with N,N-diisopropylethylamine (32.63g, 0.253 M) and (3R)-3-t-butoxycarbonylaminopyrrolidine (20.65 g, 0.111M). The mixture was stirred and heated to reflux for 18 hours. Solventwas evaporated, and the residue treated with EtOAc (300 ml) and water(200 ml). The organic laver was washed with water (1 50 ml). citric acidsolution (10% in water, 2×150 ml), and dried (magnesium sulfate).Evaporation gave the desired product as a yellow solid (32.7 g), ofsufficient quality for use without purification. MS (ESP): 326 (MH⁺) forC₁₅H₂₀FN₃O₄.

NMR(CDCl₃) δ: 1.43 (s, 9H); 1.85 (m, 1H); 2.25 (m, 1H); 3.44 (dt, 1H);3.65 (overlapping m, 2H); 3.84 (dm, 1H); 4.34 (br m, 1H); 4.69 (br, 1H);6.53 (t, 1H); 7.87 (dd, 1H); 7.92 (dd, 1H).

5-Amino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene

3-Fluoro-4-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)nitrobenzene(32.7 g, 0.101 M) was dissolved in EtOAc (500 ml) treated with palladiumcatalyst (10% on carbon, 7.5 g) and hydrogenated at atmospheric pressureuntil the theoretical uptake of gas. After filtration through celite andevaporation. the required product was obtained as a red gum ofsufficient quality for use without purification (29.85 g).

MS (ESP): 296 (MH⁺) for C₁₅H₂₂FN₃O₂; NMR (CDCl₃) δ: 1.44 (s, 9H); 1.82(m, 1H); 2.27 (m, 1H); 3.11 (m, 2H); 3.37 (m, 2H); 3.43 (br, 2H); 4.27(br m, 1H); 4.82 (br, 1H); 6.38 (dd, 1H); 6.44 (dd, 1H); 6.57 (t, 1H).

5-Ethoxycarbonylamino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene

5-Amino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene(27.33 g, 0.093 M) was dissolved in dry pyridine (150 ml) and cooledunder nitrogen with stirring to 0°. Ethyl chloroformate (11.01, 0.102 M)was added dropwise, and the mixture stirred 30 minutes at the sametemperature. Ice-water (250 ml) was added, and stirring continued for 1hour. The resulting precipitate was collected, washed thoroughly withwater, and dried, to give the desired product of sufficient quality foruse without purification (33.6 g). MS (ESP): 368 (MH⁺) for C₁₈H₂₆FN₃O₄.

NMR (DMSO-d₆) δ: 1.21 (t, 3H); 1.36 (s, 9H); 1.90 (m, 1H); 2.05 (m, 1H);3.04 (m, 1H); 3.20 (m, 1H); 3.32 (m, 1H); 3.40 (m, 1H); 4.02 (br, 1H);4.05 (q, 2H); 6.62 (t, 1H); 7.02 (d, 1H); 7.08 (d, 1H); 7.22 (d, 1H);9.38 (br, 1H).

3-(3-Fluoro-4-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Ethoxycarbonylamino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene(33.6 g, 0.092 M) was dissolved in dry tetrahydrofuran (300 ml) undernitrogen. cooled to −70°, and treated dropwise over 30 minutes with asolution of lithiun t-butoxide (1 M in tetrahydrofuran, 100.7 ml),keeping the temperature below −65°. After stirring for 5 minutes,(R)-glycidylbutyrate (14.52 g, 0.101 M) was added, and stirringcontinued at −65° for 1 hour, before allowing the temperature to rise toambient over 16 hours. The mixture was treated with MeOH (50 ml),stirred at ambient temperature for 1 hour, and the precipitate collectedand washed well with tetrahydrofuran to give the desired product (21.8g).

MS (ESP): 396 (MH⁺) for C₁₉H₂₆FN₃O₅; NMR (DMSO-d₆) δ: 1.36 (s, 9H); 1.80(m, 1H); 2.07 (m, 1H); 3.09 (m, 1H); 3.26 (t, 1H); 3.35 (m, 1H); 3.49(m, 2H); 3.62 (m, 1H); 3.73 (dd, 1H); 3.98 (t, 1H); 4.04 (m, 1H); 4.63(m, 1H); 5.15 (t, 1H); 6.70 (t, 1H); 7.09 (dd overlapping br, 2H); 7.39(dd, 1H).

3-(4-((3R)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(3-Fluoro-4-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(5 g, 12.7 mmol), 3-hydroxyisoxazole (2.15 g, 25.3 mmol), and1,1′-(azodicarbonyl)dipiperidine (6.39 g, 25.3 mmol) were suspended bystirring in dry tetrahydrofuran (100 ml) under nitrogen and cooled to 5°in an ice-bath. Tributylphosphine (5.12 g, 25.3 mmol) was added dropwiseover 20 minutes, and the solution stirred 18 hours, allowing thetemperature to rise to ambient. Reduced azo compound was filtered off,and the solution evaporated to dryness and the residue triturated withether. The residue was purified by chromatography on a 90 g Biotagesilica column, eluting with a gradient from 50 to 75% EtOAc inisohexane. Relevant fractions were combined and evaporated to give theproduct (3.92 g).

MS (ESP): 463 (MH⁺) for C₂₂H₂₇FN₄O₆; NMR (DMSO-d₆) δ: 1.38 (s, 9H); 1.81(m, 1H); 2.08 (m, 1H); 3.10 (m, 1H); 3.25 (t, 1H); 3.36 (m, 1H); 3.48(m, 1H); 3.84 (dd, 1H); 4.05 (m, 1H); 4.12 (t, 1H); 4.44 (m, 2H); 5.02(m, 1H); 6.36 (d, 1H); 6.71 (t, 1H); 7.11 (dd overlapping br, 2H); 7.38(dd, 1H); 8.66 (d, 1H).

EXAMPLE 873-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one(3.52 g, 10 mmol), 3-hydroxyisoxazole (893 mg, 10.05 mmol), andtriphenylphosphine (3.03 g, 12 mmol) were dissolved by stirring in drytetrahydrofuran (75 ml) under nitrogen. The mixture was cooled in anice-bath, and diisopropylazodicarboxylate (2.33 g, 12 mmol) addeddropwise over 10 minutes. The solution was stirred 18 hours, allowingthe temperature to rise to ambient. The mixture was diluted with EtOAc(750 ml). the organic layer washed with water (3×500 ml), dried(magnesium sulfate) and evaporated. The residue was purified by MPLC onsilica, eluting with a gradient between 0.25% and 1% MeOH indichloromethane. Relevant fractions were combined and evaporated to giveproduct (3.58 g).

MS (ESP): 420 (MH⁺) for C₂₀H₂₂FN₃O₆; NMR (DMSO-d₆) δ: 1.73 (t, 4H); 3.03(t, 4H); 3.86 (dd, 1H); 3.90 (s, 4H); 4.14 (t, 1H); 4.42 (dd, 1H); 4.47(dd, 1H); 5.03 (m, 1H); 6.35 (d, 1H); 7.08 (t, 1H); 7.17 (dd, 1H); 7.47(dd, 1H); 8.65 (d, 1H).

The intermediates for this compound were prepared as follows:

4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)-3-fluoronitrobenzene

3,4-Difluoronitrobenzene (15.53 g, 0.098 M) was dissolved inacetonitrile (150 ml), and treated with N,N-diisopropylethylamine (31.5g, 0.244 M) and 1,4-dioxa-8-azaspiro[4,5]decane (15.36 g, 0.107 M). Themixture was stirred and heated to reflux for 18 hours. After cooling,product precipitated as a yellow solid, and was filtered off (16.1 g);further product could be obtained by concentrating the residues (8.43g).

MS (ESP): 283 (MH⁺) for C₁₃H₁₅FN₂O₄; NMR (CDCl₃) δ: 1.86 (t, 4H); 3.41(t, 4H); 4.00 (s, 4H); 6.91 (t, 1H); 7.89 (dd, 1H); 7.96 (dd, 1H).

5-Amino-2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)fluoroberzene

Starting from4-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluoronitrobenzene (24.48 g,0.087 M). the title compound was prepared by essentially the samctechnique as the corresponding intermediate of Example 86 (19.3 g).

MS (ESP): 253 (MH⁺) for C₁₃H₁₇FN₂O₂; NMR (DMSO-d₆) δ: 1.69 (t, 4H); 2.84(t, 4H); 3.86 (s, 4H); 4.91 (s, 2H); 6.28 (m, 2H); 6.75 (t, 1H).

5-Ethoxycarbonylanino-2-(1,4-dioxa-8-azaspiro[4,5decan-8-yl)fluorobenzene

Starting from5-amino-2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)fluorobenzene (19.26 g,0.076 M), the title compound was prepared by essentially thc sametechnique as the corresponding intermediate of Example 86 (20.5 g).

MS (ESP): 325 (MH⁺) for C₁₆H₂₁FN₂O₄; NMR (DMSO-d₆) δ: 1.21 (t, 3H); 1.71(t, 4H); 2.96 (t, 4H); 3.88 (s, 4H); 4.09 (q, 2H); 6.95 (t, 1H); 7.09(dd, 1H); 7.27 (dd, 1H); 9.54 (s, 1H).

3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenvi)-5(R)-hydroxymethyloxazoldin-2-one

Starting from5-ethoxycarbonylarnino-2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)fluorobenzene(22.9 g, 0.071 M)), the title compound was prepared by essentially thesame technique as the corresponding intermediate of Example 86 (17.8 g).

MS (ESP): 353 (MH⁺) for C₁₇H₂₁FN₂O₅; NMR (DMSO-d₆) δ: 1.83 (t, 4H); 3.09(t, 4H); 3.69 (dd, 1H), 3.82 (dd, 1H), 3.88 (dd, 1H); 3.96 (s, 4H); 4.07(t, 1H); 4.72 (m, 1H); 4.92 (s, 1H); 7.05 (t, 1H); 7.15 (dd, 1H); 7.46(dd, 1H).

EXAMPLE 883-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(3.58 g, 8.52 mmol) was dissolved in a mixture of glacial acetic acid(50 ml) and water (50 ml), and heated at 50° for 12 hours. Solvent wasevaporated, the residue azeotroped with toluene (50 ml), thenpartitioned between EtOAc (150 ml) and water (100 ml). The organic layerwas washed with saturated aqueous sodium bicarbonate solution (2×100ml), water (100 ml), dried (magnesium sulfate) and evaporated. Theresidue was purified by chromatography on a 90 g silica Biotage columneluting with a gradient from 5:1 EtOAc to isohexane to EtOAc. Relevantfractions were combined to give the desired product (2.84 g).

MS (ESP): 376 (MH⁺) for C₁₈H₁₈FN₃O₅; NMR (CDCl₃) δ: 2.61 (t, 4H); 3.37(t, 4H); 3.93 (dd, 1H); 4.14 (t, 1H); 4.50 (dd, 1H); 4.57 (dd, 1H); 5.02(m, 1H); 6.00 (d, 1H); 6.98 (t, 1H); 7.14 (dd, 1H); 7.49 (dd, 1H); 8.15(d, 1H).

EXAMPLE 893-(4-(4-Hydroxypiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(173 mg, 0.46 mmol) was dissolved in ethanol (5 ml), treated with sodiumborohydride (18 mg, 0.48 mmol) and refluxed 1 hour. Solvent wasevaporated, the residue treated with water (5 ml), neutralised with 1 Nhydrochloric acid, extracted with dichloromethane (3×10 ml), and dried(magnesium sulfate). Evaporation gave the desired product (76 mg). MS(ESP): 378 (MH⁺) for C₁₈H₂₀FN₃O₅.

NMR (CDCl₃) δ: 1.60 (br, ˜1H); 1.76 (m, 2H); 2.05 (m, 2H); 2.85 (m, 2H);3.32 (m, 2H); 3.85 (m, 1H); 3.91 (dd, 1H); 4.12 (t, 1H); 4.48 (dd, 1H);4.55 (dd, 1H); 4.98 (m, 1H); 6.00 (d, 1H); 6.98 (br, 1H); 7.11 (dd, 1H);7.42 (dd, 1H); 8.12 (d, 1H).

EXAMPLE 903-(4-(4-Aminopiridin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(375 mg, 1 mmol) was dissolved in MeOH (10 ml), treated with ammoniumacetate (771 mg, 10 mmol) and sodium cyanoborohydride (440 mg, 7 mmol)and refluxed 4 hours. The mixture was neutralised with 1 N hydrochloricacid, water (15 ml) added, and extracted with dichloromethane (3×15 ml),and dried (magnesium sulfate). Evaporation gave the desired product (334mg).

MS (ESP): 377 (MH⁺) for C₁₈H₂₁FN₄O₄; NMR (CDCl₃) δ: 1.53 (br, 4H); 1.94(m, 2H); 2.77 (overlapping m, 3H); 3.38 (m, 2H); 3.92 (dd, 1H); 4.13 (t,1H); 4.47 (dd, 1H); 4.55 (dd, 1H); 4.99 (m, 1H); 6.00 (d, 1H); 6.94 (t,1H); 7.12 (dd, 1H); 7.40 (dd, 1H); 8.15 (d, 1H).

EXAMPLE 913-(4-(4-Hydroxyiminopiperindin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5ml), and stirred at ambient temperature under nitrogen. The mixture wastreated with hydroxylamine hydrochloride (27 mg, 0.39 mmol) and sodiumacetate (65 mg, 0.79 mmol) and stirring continued for 4 hours. Themixture was filtered, evaporated, and the residue partitioned betweenwater (10 ml), and dichloromethane (10 ml). The organic layer was washedwith saturated sodium bicarbonate (10 ml), water (10 ml), dried(magnesium sulfate) and evaporated to dryness. The residue was purifiedby chromatography on a 5 g silica Mega Bond Elut® column, eluting with1% MeOH in dichloromethane. Relevant fractions were combined to give thedesired product (74 mg). MS (ESP): 391 (MH⁺) for C₁₈H₁₉FN₄O₅.

NMR (DMSO-d₆) δ: 2.36 (t, 2H); 2.62 (t, 2H); 3.02 (t, 2H); 3.08 (t, 2H);3.87 (dd, 1H); 4.16 (t, 1H); 4.42 (dd, 1H); 4.49 (dd, 1H); 5.04 (m, 1H);6.37 (d, 1H); 7.08 (t, 1H); 7.21 (dd, 1H); 7.50 (dd, 1H); 8.67 (d, 1H);10.38 (s, 1H).

EXAMPLE 923-(4-(4-Methoxycarbonylaminoiminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5ml), methyl carbazate (34 mg, 0.37 mmol) added, and the mixture stirredat ambient temperature under nitrogen for 18 hours. The mixture wasevaporated, and the residue purified by chromatography on a 5 g silicaMega Bond Elut® column, eluting with a gradient increasing in polarityfrom 0 to 1% MeOH in dichloromethane. Relevant fractions were combinedto give the desired product (98 mg).

MS (ESP): 448 (MH⁺) for C₂₀H₂₂FN₅O₆; NMR (CDCl₃) δ: 2.53 (t, 2H); 2.67(t, 2H); 3.18 (t, 2H); 3.22 (t, 2H); 3.83 (s, 3H); 3.92 (dd, 1H); 4.14(t, 1H); 4.49 (dd, 1H); 4.57 (dd, 1H); 5.01 (m, 1H); 6.01 (d, 1H); 6.96(t, 1H); 7.13 (dd, 1H); 7.47 (dd, 1H); 7.79 (s, 1H); 8.16 (d, 1H).

EXAMPLE 933-(4-(4-(2-Hydroxyethyl)aminoiminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5ml), 2-hydroxyethylhydrazine (29 mg, 0.37 mmol) added, and the mixturestirred at ambient temperature under nitrogen for 18 hours. The mixturewas evaporated, and the residue purified by chromatography on a 5 gsilica Mega Bond Elut® column, eluting with a gradient increasing inpolarity from 0 to 1.5% MeOH in dichloromethane. Relevant fractions werecombined to give the desired product (98 mg). MS (ESP): 434 (MH⁺) forC₂₀H₂₄FN₅O₅.

NMR (DMSO-d₆) δ: 2.34 (t, 2H); 2.43 (t, 2H); 3.04 (m, 4H); 3.47 (q, 2H);3.76 (q, 1H); 3.87 (dd, 1H); 4.16 (t, 1H); 4.43 (overlapping m, 4H);5.04 (m, 1H); 5.73 (br, 1H); 6.37 (d, 1H); 7.07 (t, 1H); 7.18 (dd, 1H);7.50 (dd, 1H); 8.67 (d, 1H).

EXAMPLE 943-(4-(4-Methanesulfonaminolpiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-Aminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(249 mg, 0.66 mmol) in dichloromethane (20 ml) was cooled in anice-bath, treated with triethylamine (140 mg, 1.4 mmol) andmethanesulfonyl choride (160 mg, 1.4 mmol), and stirred 18 hours,allowing the temperature to rise to ambient. The solution was washedwith water (3×5 ml), and the residue after evaporation purified bychromatography on a 10 g silica Mega Bond Elut® column. eluting with agradient increasing in polarity from 0 to 5% MeOH in dichloromethane.Relevant fractions were combined to give the desired product (38 mg).

MS (ESP): 455 (MH⁺) for C₁₉H₂₃FN₄O₆S; NMR (CDCl₃) δ: 1.74 (m, 2H); 2.12(m, 2H); 2.78 (t, 2H); 3.01 (s, 3H); 3.34 (d, 2H); 3.47 (m, 1H); 3.91(dd, 1H); 4.12 (t, 1H); 4.34 (d, 1H); 4.48 (dd, 1H); 4.56 (dd, 1H); 4.99(m, 1H); 5.99 (d, 1H); 6.92 (t, 1H); 7.11 (dd, 1H); 7.43 (dd, 1H); 8.14(d, 1H).

EXAMPLE 953-(4-(4-Methoxycarbonylaminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 94, starting with3-(4-(4-aminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(249 mg, 0.66 mmol) and methyl chloroformate (70 mg, 0.74 mmol) in placeof methanesulfonyl choride, gave the desired product (125 mg) afterchromatography.

MS (ESP): 435 (MH⁺) for C₂₀H₂₃FN₄O₆; NMR (CDCl₃) δ: 1.65 (m, 2H); 2.06(m, 2H); 2.78 (td, 2H); 3.34 (dm, 2H); 3.67 (s overlapping br, 4H); 3.92(dd, 1H); 4.11 (t, 1H); 4.48 (dd, 1H); 4.55 (dd, 1H); 4.63 (m, 1H); 4.99(m, 1H); 5.99 (d, 1H); 6.93 (t, 1H); 7.11 (dd, 1H); 7.43 (dd, 1H); 8.15(d, 1H).

EXAMPLE 963-(4-((3R)-3-Methoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 94, starting with3-(4-((3R)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride (249 mg, 0.62 mmol), the title compound (189 mg) wasobtained without need of chromatography. MS (ESP): 441 (MH⁺) forC₁₈H₂₁FN₄O₆S; NMR (DMSO-d₆) δ: 1.94 (m, 1H); 2.25 (m, 1H); 3.02 (s, 3H);3.27 (m, 1H); 3.38 (t, 1H); 3.45 (t, 1H); 3.61 (m, 1H); 3.92 (dd, 1H);4.05 (m, 1H); 4.19 (t, 1H); 4.48 (dd, 1H); 4.54 (dd, 1H); 5.08 (m, 1H);6.37 (d, 1H); 6.83 (t, 1H); 7.19 (dd, 1H); 7.45, 7.48 (dd overlappingbr, 2H); 8.76 (d, 1H).

EXAMPLE 973-(4-((3R)-3-Methanesulfonamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 94, starting with3-(4-((3R)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride (232 mg, 0.58 mmol), and methyl chloroformate (66 mg, 0.7mmol) in place of methanesulfonyl choride, gave thc desired product (182mg) without need of chromatography.

MS (ESP): 421 (MH⁺) for C₁₉H₂₁FN₄O₆; NMR (DMSO-d₆) δ: 1.89 (m, 1H); 2.18(m, 1H); 3.21 (m, 1H); 3.36 (m, 1H); 3.43 (m, 1H); 3.56 (m, 1H); 3.59(s, 3H); 3.92 (dd, 1H); 4.19 (t overlapping m, 2H); 4.48 (dd, 1H); 4.55(dd, 1H) 5.08 (m, 1H); 6.46 (d, 1H); 6.80 (t, 1H); 7.17 (dd, 1H); 7.48(dd, 1H); 7.53 (d, 1H); 8.77 (d, 1H).

EXAMPLE 983-(3-Fluoro-4-(imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one

3-(3-Fluoro-4-(imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(WO 96/23788; 280 mg, 1 mmol), 3-hydroxyisoxazole (94 mg, 1.1 mmol), andtriphenylphosphine (330 mg, 1.25 mmol) were suspended by stirring in drytetrahydrofuran (10 ml) under nitrogen at ambient temperature.Diisopropylazodicarboxylate (308 mg, 1.5 mmol) was added dropwise over10 minutes. The suspension dissolved, and stirring was continued at thesame temperature for 2 hours. The mixture was evaporated to dryness, andthe residue purified by chromatography on a 20 g silica Mega Bond Elut®columns, eluting with a gradient increasing in polarity from 50 to 100%EtOAc in isohexane. Relevant fractions were combined and evaporated togive the desired product (206 mg). MS (ESP): 345 (MH⁺) for C₁₆H₁₃FN₄O₄.

NMR (DMSO-d₆) δ: 3.97 (dd, 1H); 4.24 (dd, 1H); 4.48 (m, 2H); 5.11 (m,1H); 6.37 (d, 1H); 7.11 (d, 1H); 7.47 (dd, 1H); 7.52 (d, 1H); 7.66 (t,1H); 7.74 (dd, 1H); 7.99 (s, 1H); 8.66 (d, 1H).

EXAMPLE 99-103

In a multiple parallel synthesis, using the conditions of thcintermediate in Example 65, the same ratios of reagents, the appropriatehydroxymethyl starting material, and purifying as before on 10 g MegaBond Elut® columns the following compounds were prepared.

Ex- Weight am- Moles of Foot ple Starting Material Used Product Productnotes  99

0.3 mmol

 20 mg 1, 6 100

0.7 mmol

 70 mg 2, 6 101

0.5 mmol

 50 mg 3, 7 102

0.6 mmol

110 mg 4, 8 103

0.2 mmol

 70 mg 5, 9 Footnotes: 1. MS (ESP): 346 (MH⁺) for C₁₅H₁₂FN₅O₄ 2. MS(ESP): 346 (MH⁺) for C₁₅H₁₂FN₅O₄ NMR (DMSO-d₆) δ: 3.97(dd, 1H); 4.26(dd,1H); 4.48(m, 2H); 5.11(m, 1H); 6.37(d, 1H); 7.53(dd, 1H); 7.74(dd, 1H);7.83(t, 1H); 8.13(s, 2H); 8.69(d, 1H). 3. MS (ESP): 326 (MH⁺) forC₁₇H₁₅N₃O₄ NMR (DMSO-d₆) δ: 3.93(dd, 1H); 4.22(t, 1H); 4.47(m, 2H);5.06(m 1H); 6.22(m, 2H); 6.37(d, 1H); 7.31(m, 2H); 7.60(dd, 4H); 8.68(d,1H). 4. MS (ESP): 369 (MH⁺) for C₁₈H₁₃FN₄O₄ NMR (DMSO-d₆) δ: 3.96(dd,1H); 4.23(t, 1H); 4.47(m, 2H); 5.10(m, 1H); 6.37(d, 1H); 6.70(m, 1H);7.28(m, 1H); 7.47(dd, 1H); 7.64(t, 1H); 7.74(dd, 1H); 7.99(m, 1H);8.67(d, 1H). 5. MS (ESP): 405 (MH⁺) for C₁₉H₂₁FN₄O₅ NMR (DMSO-d₆) δ:1.04(t, 3H); 3.35(t + m, 6H); 3.59(s, 2H); 3.87(dd, 1H); 4.16(t, 1H);4.45(m, 2H); 5.03(m, 1H); 6.36(d, 1H); 7.05(t, 1H); 7.21(dd, 1H);7.53(dd, 1H); 8.68(d, 1H). 6. Starting material described in WO96/23788. 7. The intermediate for this compound was prepared as follows:

1-(4-Ethoxycarbonylaminophenyl)pyrrole

Ethyl chloroforrnate (0.38 ml) was added dropwisc to a stirred solutionof 1-(4-aminophenyl)pyrrole (0.56 g, 3.54 mmol , Corelli et al.,Farmaco. Ed. Sci., 1983, 38, 219) in pyridine (5 ml) at 5-10° C. for 15minutes. The cooling bath was removed and stirring continued for 1.5hours. The mixture was evaporated and the residue was purified by flashcolumn chromatography on silica gel, eluting with a gradient of 1-4%MeOH in dichloromethane to give the title product (0.43 g) as a solid.

MS (ESP): (MH⁺) 231 for C₁₃H₁₄N₂O₂; NMR (CDCl₃) δ: 1.33 (t, 3H); 4.25(q, 2H); 6.32 (t, 2H); 6.60 (s, 1H); 7.02 (t, 2H); 7.32-7.42 (m, 4H).

(5S)-3-(4-(1-Pyrrolyl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one

To a solution of 1-(4-ethoxycarbonylaminophenyl)pyrrole (0.45 g, 2.14mmol) in dry tetrahydrofuran (30 ml) at −60° C. under nitrogen, wasadded dropwise a solution of n-butyl lithium in (1.6 M in isohexane, 1.3ml). The mixture was stirred for 20 minutes before (R)-glycidylbutyrate(0.3 g, 2.1 mmol) in tetrahydrofuran (2 ml) was added dropwise. Themixture was allowed to warm to room temperature, stirred for 16 hoursand partitioned between EtOAc and saturated ammonium chloride solution.The organic layer was washed with brine, dried (magnesium sulfate) andevaporated. The residue was recrystallised from ethanol to give thetitle product (0.21 g), mp 179-181° C. MS (ESP): 259 (MH⁺) forC₁₄H₁₄N₂O₃;

NMR (DMSO-d₆) δ: 3.5-3.75 (m, 2H); 3.87 (m, 1H); 4.12 (t, 1H); 4.70 (m,1H); 5.18 (t, 1H); 6.24 (t, 2H); 7.31 (t, 2H); 7.5-7.7 (m, 4H).C₁₄H₁₄N₂O₃ requires C: 65.1, H: 5.46, N: 10.8%; found: C: 64.5, H: 5.5,N: 10.6%.

8. The intermediate for this compound was prepared as follows:

3-Fluoro-4-(3-cyano-1-pyrrolyl)nitrobenzene

3-Cyanopyrrole (3.6 g, 39.1 mmol , CE Loader et al, Can. J. Chem., 1981,59, 2673) and 3,4-difluoronitrobenzene (6.5 g, 40.9 mmol) were dissolvedin DMF (50 ml) and cooled in an ice-bath. The mixture was stirred andsodium hydride (60% in oil, 1.6 g, 40 mmol) added over 20 minutes. Afterallowing the mixture to come to ambient temperature, it was heated to650 for 1 hour. Solvent was evaporated, the residue triturated withwater, and filtered. The crude solide was purified by flashchromatography on silica, eluting with dichloromethane. Relevantfractions were combined to give the title product (3.75 g), mp 117-119°.

MS (ESP): 230 (MH⁻) for C₁₁H₆FN₃O₂; NMR (CDCl₃) δ: 6.68 (s, 1H); 7.09(m, 1H); 7.61 (overlapping m, 2H); 8.20 (overlapping m, 2H).

5-Amino-2-(3-cyano-1-pyrrolyl)fluorobenzene

3-Fluoro-4-(3-cyano-1-pyrrolyl)nitrobenzene (5.3 g, 22.9 mmnol) wasdissolved in hot MeOH (250 ml) and palladium catalyst (10% on charcoal,700 mg) added under a nitrogen atmosphere. The mixture was cooled andhydrogenated at atmospheric pressure for 3.5 hours. After filtrationthrough celite, the solution was evaporated to dryness to give titleproduct in sufficent purity for the next stage (4.6 g).

MS (ESP): 202 (MH⁺) for C₁₁H₈FN₃; NMR (CDCl₃) δ: 3.93 (br s, 2H); 6.50(m, 3H); 6.82 (s, 1H); 7.10 (t, 1H); 7.31 (s, 1H).

5-Ethoxycarbonylamino-2-(3-cyano-1-pyrrolyl)fluorobenzene

5-Amino-2-(3-cyano-1-pyrrolyl)fluorobenzene (4.6 g, 22.9 mmol) wasstirred in dry pyridine (50 ml) 0°. Ethyl chloroformate (2.66 g, 24.5mmol) was added, and stirring continued for 20 minutes at the sametemperature before allowing the temperature to rise to ambient over 2hours. Solvent was evaporated, the residue treated with iced water (50ml), filtered off, and dried. Crystallisation of the crude product fromethanol (200 ml) gave the title product (4.9 g) mp 188-190°.

MS (ESP): 274 (MH⁻) for C₁₄H₁₂FN₃O₂; NMR (DMSO-d₆) δ: 1.26 (t, 3H); 4.16(q, 2); 6.69 (m, 1H); 7.23 (m, 1H); 7.33 (dd, 1H); 7.53 (t, 1H); 7.59(dd, 1H); 7.92 (m, 1H); 10.04 (br s, 1H).

(5S)-3-(3-Fluoro-4-(3-cyano-1-pyrrolyl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Ethoxycarbonylamino-2-(3-cyano-1-pyrrolyl)fluorobenzene (4.8 g, 17.6mmol) was dissolved in dry tetrahydrofuran (200 ml) under nitrogen,cooled to −70°, and treated with a solution of n-butyllithium (1.6 M inisohexane, 11.0 ml). After stirring for 45 minutes at −70°,(R)-glycidylbutyrate (2.8 g, 19.4 mmol) dissolved in tetrahydrofuran (5ml) was added at −70°. Stirring was continued for 18 hours allowing thetemperature to rise to ambient. Saturated ammonium chloride solution (50ml) was added and the mixture extracted with EtOAc (250 ml, then 2×100ml). The combined extracts were washed with brine (60 ml), dried(magnesium sulfate) and evaporated, and the residue purified bycrystallisation from ethanol to give the desired product (3.9 g), mp157-159°, MS (ESP): 302 (MH⁺) for C₁₅H₁₂FN₃O₃.

NMR (DMSO-d₆) δ: 3.58 (dd, 1H); 3.71 (dd, 1H); 3.88 (dd, 1H); 4.14 (t,1H); 4.75 (m, 1H); 5.21 (t, 1H); 6.72 (m, 1H); 7.28 (m, 1H); 7.49 (dd,1H); 7.65 (t, 1H); 7.76 (dd, 1H); 7.79 (m, 1H).

9. Starting material described in WO 97/27188.

EXAMPLE 1043-(4-(4-Hydroxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(0.59 g, 1.2 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to0°. A solution of tetra-n-butylarnmonium fluoride (1 M, 5 ml, 5 mmol)was added and the mixture stirred 3 hours as the temperature rose toambient. The mixture was evaporated to drvness, redissolved indichloromethane (50 ml), washed with water (3×25 ml), and dried overmagnesium sulfate. After filtration and evaporation the residue waspurified by chromatography on a 10 g silica Mega Bond Elut® column.cluting with a gradient increasing in polarity from 0 to 10% MeOH indichloromethane. Relevant fractions were combined and evaporated to givethe desired product (245 mg). MS (ESP): 375 (MH⁺) for C₁₇H₁₅FN₄O₅.

NMR (DMSO-d₆) δ: 3.96 (dd, 1H); 4.26 (t, 1H); 4.40 (d, 2H); 4.48 (m,2H); 4.99 (t, 1H); 5.11 (m, 1H); 6.39 (d, 1H); 7.35 (s, 1H); 7.47 (dd,1H); 7.66 (t, 1H); 7.75 (dd, 1H); 7.93 (s, 1H); 8.70 (d, 1H).

The intermediate for this compound was prepared as follows.

3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-hydroxy-methyloxazolidin-2-one(WO 99/10343, 1.57 g, 3.72 mmol), 3-hydroxyisoxazole (350 mg, 4.1 mmol),and tributylphosphine (934 mg, 4.6 mmol) were dissolved by stirring indry tetrahydrofuran (100 ml) under nitrogen. The mixture was cooled inan ice-bath, and 1,1′-(azodicarbonyl)dipiperidine (1.16 g, 4.6 mmol)added dropwise over 10 minutes. The solution was stirred 18 hours,allowing the temperature to rise to ambient. Reduced azo compound wasfiltered off, and the solution evaporated to dryness and the residuetriturated with ether. The ether layer was evaporated, dissolved indichloromethane and purified by chromatography on a 40 g silica MegaBond Elut® column, eluting with a dichloromethane, then 1% MeOH indichloromethane. Relevant fractions were combined and evaporated to give(5S)-3-(4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-oneas an oil (0.59 g).

MS (ESP): 489 (MH⁺) for C₂₃H₂₉FN₄O₅Si; NMR (CDCl₃) δ: 0.00 (s, 6H); 0.79(s, 9H); 3.90 (dd, 1H); 4.07 (t, 1H); 4.38 (dd, 1H); 4.48 (dd, 1H); 4.63(s, 2H); 4.92 (m, 1H); 5.88 (d, 1H); 6.98 (s, 1H); 7.21 (dd, 1H); 7.27(t, 1H); 7.57 (dd, 1H); 7.61 (s, 1H); 8.03 (d, 1H).

EXAMPLE 1053-(3-Fluoro-4-(2-methyl-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yl-oxymethyl)oxazolidin-2-one

Using essentially the same procedure as for the intermediate of Example65, but starting with3-(3-fluoro-4-(2-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(202 mg, 0.69 mmol), and purifying by chromatography on a 10 g silicaMega Bond Elut® column, eluting with a gradient increasing in polarityfrom 0 to 2.5% MeOH in dichloromethane, the title compound was prepared(137 mg).

MS (ESP): 359 (MH⁺) for C₁₇H₁₅FN₄O₄; NMR (DMSO-d₆) δ: 2.16 (s, 3H); 4.00(dd, 1H); 4.27 (t, 1H); 4.49 (m, 2H); 5.12 (m, 1H); 6.40 (d, 1H); 6.94(d, 1H); 7.23 (d, 1H); 7.50 (dd, 1H); 7.57 (t, 1H); 7.77 (dd, 1H); 8.71(d, 1H).

The intermediates for this compound were prepared as follows:

3-Fluoro-4-(2-methyl-imidazol-1-yl)nitrobenzene

2-Methylimidazole (9.02 g, 0.11 M) and N,N-diisopropylethylamine (32.2g, 0.25 M) were dissolved in acetonitrile (160 ml), and3.4-difluoronitrobenzene (15.9 g, 0.1 M) added. The mixture was stirredand heated to reflux under nitrogen for 24 hours. Solvent wasevaporated, the residue dissolved in EtOAc (300 ml), washed with water(150 ml), brine (150 ml), and dried (magnesium sulfate). The residue wasrecrystallised from a mixture of EtOAc (25 ml) and cyclohexane (150 ml)with the addition of charcoal to give the title compound (11.5 g), mp106-107°.

MS (ESP): 222 (MH⁺) for C₁₀H₈FN₃O₂; NMR (DMSO-d₆) δ: 2.25 (s, 3H); 7.00(d, 1H); 7.35 (t, 1H); 7.87 (t, 1H); 8.23 (dd, 1H); 8.43 (dd, 1H).

5-Amino-2-(2-methyl-imidazol-1-yl)fluorobenzene

3-Fluoro4-(2-methyl-imidazol-1-yl)nitrobenzene (40 g, 0.181 M) wasdissolved in a mixture of MeOH (200 ml) and tetrahydrofuran (800 ml),cooled to 0° under nitrogen, and treated with ammonium formate (57 g,0.905 M) followed by palladium on charcoal (10%, 2 g). The mixture wasstirred at ambient temperature for 18 hours, filtered through celite,celite washed with MeOH (100 ml), and filtrate evaporated to dryness.The residue was partitioned between EtOAc (800 ml) and 10% aqueoussodium bicarbonate (250 ml). The organic layer was separated, washedwith brine (250 ml), dried (magnesium sulfate) and evaporated to givetitle compound (34.6 g).

MS (ESP): 192 (MH⁺) for C₁₀H₁₀FN₃; NMR (DMSO-d₆) δ: 2.08 (s, 3H); 5.68(s, 2H); 6.45 (overlapping m, 2H); 6.84 (d, 1H); 7.03 (overlapping m,2H).

5-Benzyloxycarbonylamino-2-(2-methyl-imidazol-1-yl)fluorobenzene

5-Amino-2-(2-methyl-imidazol-1-yl)fluorobenzene (34.25 g, 0.179 M) wasdissolved in dry dichloromethane (600 ml) under nitrogen, and cooled to−5°. Pyridine (17.7 g, 0.224 M) was added, followed by benzylchloroformate (33.7 g, 0.197 M) over 20 minutes. The mixture was stirredand the temperature allowed to rise to ambient over 16 hours. Aqueoussodium bicarbonate (5%, 250 ml) was added, the organic layer separated,the aqueous layer re-extracted with dichloromethane (2×300 ml), andcombined extracts dried (magnesium sulfate). After filtration andevaporation, the residue was recrystallised from toluene (400 ml) togive title product (54.5 g).

MS (ESP): 326 (MH⁻) for C₁₈H₁₆FN₃O₂; NMR (DMSO-d₆) δ: 2.13 (s, 3H); 5.18(s, 2H); 6.89 (s, 1H); 7.17 (s, 1H); 7.41 (overlapping m, 7H); 7.73 (dd,1H); 10.21 (br, 1H).

(5S)-3-(3-Fluoro-4-(2-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Benzyloxycarbonylamino-2-(2-methyl-imidazol-1-yl)fluorobenzene (54 g,0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and1,3-dimethyl-2,4,5,6-tetrahydro-2(1H)-pyrimidinonc (100 ml) undernitrogen, cooled to −70°, and treated with a solution of n-butyllithium(1.6 M in isohexane, 114 ml), over 30 minutes. After stirring for 30minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M)in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring wascontinued for 16 hours allowing the temperature to rise to ambient. Themixture was treated with aqueous sodium bicarbonate (5%, 500 ml) andEtOAc (800 ml), the organic layer separated, and the aqueous extractedwith further EtOAc (3×750 ml). The combined extracts were dried(magnesium sulfate) and evaporated, and the resulting oil trituratedwith diethyl ether. The resulting solid was recrystallisd fromisopropanol to give the title compound (21.5 g). MS (ESP): 292 (MH⁺) forC₁₄H₁₄FN₃O₃.

NMR (DMSO-d₆) δ: 2.16 (s, 3H); 3.56 (dt, 1H); 3.69 (dt, 1H); 3.88 (dd,1H); 4.15 (t, 1H); 4.74 (m, 1H); 5.24 (t, 1H); 6.92 (s, 1H); 7.20 (s,1H); 7.48 (dd, 1H); 7.53 (t, 1H); 7.74 (dd, 1H).

EXAMPLE 1063-(3-Fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yl-oxymethyl)oxazolidin-2-one

Using essentially the same procedure as for the intermediate of Example65, but starting with3-(3-fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(see Example 141; 81 mg, 0.29 mmol), and purifying by chromatography ona 5 g silica Mega Bond Elut® column, eluting with a gradient increasingin polarity from 0 to 2.5% MeOH in dichloromethane, gave the titlecompound (80 mg). MS (ESP): 359 (MH⁺) for C₁₇H₁₅FN₄O₄.

NMR (CDCl₃) δ: 2.30 (s, 3H); 4.02 (dd, 1H); 4.23 (t, 1H); 4.52 (dd, 1H);4.60 (dd, 1H); 5.07 (m, 1H); 6.00 (d, 1H); 6.94 (s, 1H); 7.50(overlapping m, 2H); 7.69 (dd, 1H); 7.77 (s, 1H); 8.16 (d, 1H).

EXAMPLE 1073-(3-Fluoro-4-(4-cyano-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(3-Fluoro-4-(4-hydroximinomethyl-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one(360 mg, 0.93 mmol) and acetic anhydride (3 ml) were heated undernitrogen at reflux for 2 hours. After cooling and pouring onto ice, themixture was extracted into dichloromethane (3×15 ml). dried (magnesiumsulfate) and evaporated. The residue was purified by chromatography on a10 g silica Mega Bond Elut® column, eluting with a gradient increasingin polarity from 0 to 2.5% MeOH in dichloromethane, to give the desiredcompound (135 mg).

MS (ESP): 370 (MH⁺) for C₁₇H₁₂FN₅O₄; NMR (DMSO-d₆) δ: 3.99 (dd, 1H);4.27 (t, 1H); 4.49 (m, 2H); 5.12 (m, 1H); 6.37 (d, 1H); 7.52 (dd, 1H);7.74 (t, 1H); 7.82 (dd, 1H); 8.29 (d, 1H); 8.56 (t, 1H); 8.69 (d, 1H).

The intermediate for this compound was prepared as follows:

3-(3-Fluoro-4-(4-aldehydo-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(WO 99/10343; 460 mg, 1.24 mmol), was dissolved in a mixture of ethanol(10 ml) and water (2 ml), and treated with hydroxylamine hydrochloride(86 mg, 1.24 mmol) and triethylamine (176 mg, 1.74 mmol). After stirringfor 18 hours at ambient temperature the precipitated solid was filteredoff, and the residue evaporated to dryness. Residue and precipitate werecombined, washed with water (2×25 ml) and dried at 70° to give3-(3-fluoro-4-(4-hydroximinomethyl-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one(361 mg) as a 3:1 mixture of E and Z isomers. MS (ESP): 388 (MH⁺) forC₁₇H₁₄FN₅O₅.

NMR (DMSO-d₆) δ: 3.97 (dd, 1H); 4.26 (t, 1H); 4.45 (dd, 2H); 5.11 (m,1H); 6.39 (d, 1H); 7.44 (s, 0.25H); 7.49 (dd, 1H); 7.73 (t, 1H); 7.77(dd+s, 1.75H); 8.00 (s, 0.75H); 8.06 (s, 0.75H); 8.10 (s, 0.25H); 8.13(s, 0.25H); 8.70 (d, 1H); 10.91 (s, 0.75H); 11.60 (s, 0.25H).

EXAMPLE 1083-(4-(Imidazol-1-yl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)-oxymethyl)oxazolidin-2-one

3-(4-(imidazol-1-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one(WO 96/23788; 500 mg, 1.8 mmol), 3-hydroxy-1,2,5-thiadiazole (221 mg,2.17 mmol), and triphenylphosphine (707 mg, 2.7 mmol) were suspended indry tetrahydrofuran (15 ml) under nitrogen by stirring. The mixture wascooled in an ice-bath and diisopropylazodicarboxylate (545 mg, 2.7 mmol)added dropwise over 10 minutes. The solution was stirred 18 hours,allowing the temperature to rise to ambient. The mixture was dilutedwith dichloromethane (200 ml), and extracted with hydrochloric acid (1M, 200 ml). The aqueous layer was washed with dichloromethane (2×100ml), and the aqueous layer made basic with the minimum of concentratedarnmonia solution. Organic material was extracted into dichloromethane(200 then 100 ml), dried (magnesium sulfate), and purified bychromatography on a 20 g silica Mega Bond Elut® column, eluting with agradient increasing in polarity from 0 to 10% MeOH in dichloromethane.Relevant fractions were combined and evaporated to give the product (520mg).

MS (ESP): 362 (MH⁺) for C₁₅H₁₂FN₅O₃S; NMR (DMSO-d₆) δ: 4.02 (dd, 1H);4.26 (t, 1H); 4.66 (d, 1H); 4.71 (d, 1H); 5.15 (m, 1H); 7.11 (t, 1H);7.48 (dd, 1H); 7.52 (m, 1H); 7.66 (t, 1H); 7.74 (dd, 1H); 7.98 (m, 1H);8.43 (s, 1H).

EXAMPLE 1093-(4-((3R)-3-Hydroxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3R)-3-t-Butyldimethylsilyloxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(1.8 g, 3.77 mmol) was stirred in a mixture of acetic acid, water, andtetrahydroftiran (3:1:1, 40 ml) at 90° for four hours. Solvent wasevaporated, and the residue purified by chromatography on a 10 g silicaMega Bond Elut® column, eluting with a gradient increasing in polarityfrom 0 to 10% MeOH in dichloromethane. Relevant fractions were combinedand evaporated to givc the desired product (420 mg) as a foam. MS (ESP):364 (MH⁺) for C₁₇H₁₈FN₃O₅.

NMR (DMSO-d₆) δ: 1.82 (m, 1H); 1.97 (m, 1H); 3.10 (d, 1H); 3.25 (t, 1H);3.40 (dd, 1H); 3.50 (m, 1H); 3.84 (dd, 1H); 4.12 (t, 1H); 4.32 (br, 1H);4.43 (m, 2H); 4.87 (d, 1H); 5.02 (m, 1H); 6.36 (d, 1H); 6.70 (t, 1H);7.10 (dd, 1H); 7.38 (dd, 1H); 8.67 (d, 1H).

The intermnediates for this compound were prepared as follows:

3-Fluoro-4-((3R)-3-hydroxy-1-pyrrolidinyl)nitrobenzene

(3R)-3-Hydroxypyrrolidine hydrochloride (20 g, 0.163 M) was suspended bystirring in acetonitrile (200 ml) under nitrogen at 50°, and treatedwith N,N-diisopropylethylarnine (52.5 g, 0.41 M) and3,4-difluoronitrobenzene (25.9 g, 0.153 M). The mixture was heated at90° for 17 hours, then the solvent evaporated. The residue was dissolvedin dichloromethane (500 ml) and washed with 5% aqueous sodium dihydrogenphosphate (300 ml), which caused partial precipitation. The precipitatewas filtered, washed, and the combined aqueous layers re-extracted withdichloromethane (200 ml). The organic layers were evaporated, and theresidue combined with the previously filtered material, and dried byazeotroping with toluene to give the desired product (35 g), ofsufficient quality for use without purification.

MS (ESP): 227 (MH⁺) for C₁₀H₁₁FN₂O₃; NMR (CDCl₃) δ: 1.89 (m, 1H); 1.97(m, 1H); 3.47 (d, 1H); 3.61 (overlapping m, 3H); 4.35 (br m, 1H); 5.03(d, 1H); 6.73 (t, 1H); 7.89 (overlapping m, 2H).

3-Fluoro-4-((3R)-3-t-butyldimethylsilyloxy-1-pyrrolidinyl)nitrobenzene

3-Fluoro-4-((3R)-3-hydroxy-1-pyrrolidinyl)nitrobenzene (35.8 g, 0.158 M)was dissolved in DMF (200 ml), and treated with imidazole (21.6 g, 0.318M) and t-butyldimethylsilyl chloride (35.7 g, 0.239 M) and stirred for18 hours at ambient temperature under nitrogen. Solvent was evaporated,and the residue treated with EtOAc (300 ml) and water (200 ml). Theorganic layer was washed with water (150 ml) and dried (magnesiumsulfate). Evaporation gave the desired product (54 g), of sufficientquality for use without purification.

MS (ESP): 341 (MH⁺) for C₁₆H₂₅FN₂O₃Si; NMR (CDCl₃) δ: 0.02 (2×s, 6H);0.74 (s, 9H); 1.79 (br m, 1H); 1.97 (m, 1H); 3.27 (d, 1H); 3.53 (m, 2H);3.68 (dt, 1H); 4.48 (br m, 1H); 6.69 (t, 1H); 7.83 (overlapping m, 2H).

5-Amino-2-((3R)-3-t-butyldimethylsilyloxy-1-nyrrolidinyl)fluorobenzene

3-Fluoro-4-((3R)-3-t-butyldimethylsilyloxy-1-pyrrolidinyl)nitrobenzene(54 g, 0.158 M) was treated in essentially the same way as theappropriate intermediate of Example 86, to give desired product requiredproduct of sufficient quality for use without purification (49 g). MS(ESP): 311 (MH⁺) for C₁₆H₂₇FN₂OSi.

NMR (DMSO-d₆) δ: 0.00 (2×s, 6H); 0.79 (s, 9H); 1.66 (m, 1H); 2.01 (m,1H); 2.84 (d, 1H); 3.02 (dd, 1H); 3.12 (dd, 1H), 3.32 (m, 1H); 4.41 (m,1H); 4.63 (s, 2H); 6.22 (dd, 1H); 6.29 (dd, 1H); 6.49 (t, 1H).

5-Ethoxycarbonylamino-2-((3R)-3-t-butyldimethylsilyloxy-1-pyrrolidinyl)fluorobenzenc

5-Amino-2-((3R)-3-t-butyldimethylsilyloxy-1-pyrrolidinyl)fluorobenzene(49 g, 0.158 M) was treated in essentially the same way as theappropriate intermediate of Example 86, except that the product wasisolated by extraction into dichloromethane, azeotroping with toluene,and crude product purified by dry column chromatography on silica,eluting with a gradient from 0-20% EtOAc in dichloromethane. Appropriatefractions were combined to give the desired product (29.6 g)

MS (ESP): 383 (MH⁺) for C₁₉H₃₁FN₂O₃Si; MR (DMSO-d₆) δ: −0.02 (s, 3H);0.01 (s, 3H); 0.78 (s, 9H); 1.16 (t, 3H); 1.72 (m, 1H); 1.98 (m, 1H);2.97 (d, 1H); 3.18 (m, 1H); 3.27 (dd, 1H); 3.48 (m, 1H); 4.02 (q, 2H);4.43 (m, 1H); 6.59 (t, 1H); 6.96 (dd, 1H); 7.17 (dd, 1H); 9.31 (s, 1H).

3-(4-((3R)-3-t-Butyldimethylsilyloxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Ethoxycarbonylamino-2-((3R)-3-t-butyldimethylsilyloxy-1-pyrrolidinyl)fluorobenzene(29.4 g, 0.077 M) was treated in essentially the same way as theappropriate intermediate of Example 86, except that the product wasisolated by extraction into EtOAc, and crude product purified by drycolumn chromatography on silica, eluting with a gradient from 0-20% MeOHin dichloromethane. Appropriate fractions were combined to give thedesired product (29.6 g).

MS (ESP): 411 (MH⁺) for C₂₀H₃₁FN₂O₄Si; NMR (DMSO-d₆) δ: −0.01 (s, 3H);0.02 (s, 3H); 0.79 (s, 9H); 1.73 (m, 1H); 2.00 (m, 1H); 3.02 (d, 1H);3.23 (m overlapped by H₂O, 1H); 3.32 (dd, 1H); 3.50 (m, 2H); 3.57 (m,1H); 3.69 (dd, 1H); 3.94 (t, 1H); 4.44 (m, 1H); 4.58 (m, 1H); 5.09 (t,1H); 6.67 (t, 1H); 7.03 (dd, 1H); 7.34 (dd, 1H).

3-(4-((3R)-3-t-Butyldimethylsilyloxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3R)-3-t-Butyldimethylsilyloxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one(4.1 g, 10 mmol) was treated essentially as in Example 67, then purifiedby flash chromatography on silica, eluting with a gradient from 0-50%EtOAc in dichloromethanc, to give the desired product (2.0 g).

MS (ESP): 478 (MH⁺) for C₂₃H₃₂FN₃O₅Si; NMR (DMSO-d₆) δ: 0.10 (s, 3H);0.12 (s, 3H); 0.87 (s, 9H); 1.84 (m, 1H); 2.09 (m, 1H); 3.13 (d, 1H);3.33 (m overlapped by H₂O, 1H); 3.43 (dd, 1H); 3.61 (m, 1H); 3.89 (dd,1H); 4.18 (t, 1H), 4.49 (m, 2H); 4.55 (m, 1H); 5.07 (m, 1H); 6.44 (d,1H); 6.78 (t, 1H); 7.15 (dd, 1H); 7.44 (dd, 1H); 8.72 (d, 1H).

EXAMPLE 1103-(4-(3-Oxo-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3R)-3-Hydroxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one(700 mg, 1.9 mmol) was dissolved in DMSO(5 ml) under nitrogen andtriethylamine (2.03 g, 20 mmol) added. A solution of sulfur trioxidepyridine complex (0.95 g, 6 mmol) in DMSO(5 ml) was added dropwise over20 minutes. After stirring 1 hour at ambient temperature, the mixturewas diluted with water (100 ml) and extracted into EtOAc (150 ml). Theorganics were washed with water (2×50 ml), brine (50 ml) and dried(magnesium sulfate). After evaporation, the residue was purified bychromatography on a 20 g silica Mega Bond Elut® column, eluting with agradient increasing in polarity from 0 to 3% MeOH in dichloromethane.Relevant fractions were combined and evaporated, and the residuecrystallised from ethanol (35 ml) to give product (176 mg). MS (ESP):362 (MH⁺) for C₁₇H₁₆FN₃O₅.

NMR (DMSO-d₆) δ: 2.58 (t, 2H); 3.60 (t, 2H); 3.66 (d, 2H); 3.87 (dd,1H); 4.15 (t, 1H); 4.45 (m, 2H); 5.03 (m, 1H); 6.36 (d, 1H); 6.94 (t,1H); 7.20 (dd, 1H); 7.47 (dd, 1H); 8.67 (d, 1H).

EXAMPLE 1113-(4-(3-Oximino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(3-Oxo-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(124 mg, 0.34 mmol) was dissolved in a mixture of dichloromethane (10ml) and MeOH (10 ml), and treated with a solution of hydroxylaminehydrochloride (220 mg, 3.17 mmol) and sodium acetate (500 mg) in water(2 ml). After stirring at ambient temperature for 4 hours, solvents wereevaporated, and the residue triturated with water (10 ml), solidfiltered and dried to give the desired product (118 mg) as a singleisomer of unknown geometry. MS (ESP): 377 (MH⁺) for C₁₇H₁₇FN₄O₅.

NMR (DMSO-d₆) δ: 2.67 (t, 2H); 3.41 (dd, 2H); 3.88 (dd, 1H); 3.96 (s,2H); 4.16 (t, 1H); 4.46 (m, 2H); 5.04 (m, 1H); 6.38 (d, 1H); 6.91 (m,1H); 7.18 (dd, 1H); 7.48 (dd, 1H); 8.69 (d, 1H); 10.72 (s, 1H).

EXAMPLE 1123-(4-((3S)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3S)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(2.1 g, 4.54 mmol) was suspended by stirring in dichloromethane (10 ml)under nitrogen and treated with a solution of hydrogen chloride inethanol (4M, 50 ml) at ambient temperature. The mixture was stirred 1hour, evaporated to a small volume, and treated with a mixture ofdichloromethane (30 ml) and diethyl ether (30 ml). The precipitate wasfiltered and washed with diethyl ether to give the title compound as itshydrochloride (2.0 g).

MS (ESP): 363 (MH⁺) for C₁₇H₁₉FN₄O₄; NMR (DMSO-d₆) δ: 2.03 (m, 1H); 2.25(m, 1H); 3.26 (dd, 1H); 3.42 (m, 1H); 3.52 (m, 2H); 3.83 (dd overlappingm, 2H); 4.13 (t, 1H); 4.42 (m, 2H); 5.02 (m, 1H); 6.37 (d, 1H); 6.79 (t,1H); 7.14 (dd, 1H); 7.44 (dd, 1H); 8.43 (br, 3H); 8.68 (d, 1H).

The intermediates for this compound were prepared as follows:

3-Fluoro-4-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)nitrobenzene

Using essentially the technique for the equivalent intermediate inExample 86,but starting from (3S)-3-t-butoxycarbonylaminopyrrolidine (20g, 0.108 M), gave the desired product as a yellow solid (33.5 g), ofsufficient quality for use without purification. MS (ESP): 326 (MH⁺) forC₁₅H₂₀FN₃O₄.

NMR (DMSO-d₆) δ: 1.36 (s, 9H); 1.87 (m, 1H); 2.08 (m, 1H); 3.36 (m, 1H);3.54 (m, 1H); 3.62 (tm, 1H); 3.73 (m, 1H); 4.09 (m, 1H); 6.72 (t, 1H);7.19 (d, 1H); 7.88 (overlapping m, 2H).

5-Amino-2-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene

Using essentially the technique for the equivalent intermediate inExample 86, but starting from3-fluoro-4-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)nitrobenzene(33.5 g, 0.103 M), gave the desired product as an oil of sufficientquality for use without purification (˜30 g). MS (ESP): 296 (MH⁺) forC₁₅H₂₂FN₃O₂.

NMR (DMSO-d₆) δ: 1.35 (s, 9H); 1.71 (m, 1H); 2.06 (m, 1H); 2.87 (dd,1H); 3.05 (m, 1H); 3.11 (m, 1H); 3.26 (m overlapping H₂O, ˜1H); 3.97 (m,1H); 4.68 (s, 2H); 6.25 (dd, 1H); 6.31 (dd, 1H); 6.51 (t, 1H); 7.03 (d,1H).

5-Ethoxycarbonylamino-2-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene

Using essentially the technique for the equivalent intermediate inExample 86, but starting from5-amino-2-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene(30.4 g, 0.103 M), gave crude product after precipitation. This waspurified by dissolving in toluene (500 ml), azeotroping until productbegan to precipitate, then cooling and adding isohexane (500 ml) tocomplete precipitation. Filtration gave the desired product (35.3 g). MS(ESP): 368 (MH⁺) for C₁₈H₂₆FN₃O₄.

NMR (DMSO-d₆) δ: 1.21 (t, 3H); 1.37 (s, 9H); 1.77 (m, 1H); 2.06 (m, 1H);3.04 (m, 1H); 3.20 (dd, 1H); 3.30 (m overlapping H₂O, 1H); 3.42 (tm,1H); 4.02 (br, 1H); 4.08 (q, 2H); 6.63 (t, 1H); 7.02 (d, 1H) 7.08 (br,1H); 7.22 (d, 1H); 9.38 (s, 1H).

3-(3-Fluoro-4-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Ethoxycarbonylamino-2-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene(35.2 g, 0.096 M) was dissolved in dry tetrahydrofuran (400 ml) undernitrogen, cooled to −70°, and treated dropwise over 20 minutes with asolution of lithium t-butoxide, prepared from t-butanol (9.3 g, 123mmol) in dry tetrahydrofuran (70 ml) and n-butyl lithium (66 ml, 1.6 Min isohexane). After stirring for 20 minutes, (R)-glycidylbutyrate (15.2g, 0.102 M) in tetrahydrofuran (20 ml) was added over 10 minutes, andthe temperature allowed to rise to ambient over 16 hours. The mixturewas treated with MeOH (10 ml), stirred at ambient temperature for 10minutes. then treated with a mixture of 5% aqueous sodium bicarbonate(250 ml) and EtOAc (500 ml). The precipitate was collected and washedwell with EtOAc and water to give the desired product (19.5 g). Thefiltrate was separated into an organic layer, which was dried (magnesiumsulfate) and evaporated. The residue was refluxed briefly with EtOAc(100 ml), cooled, and filtered to give further product (16.6 g).

MS (ESP): 396 (MH⁺) for C₁₉H₂₆FN₃O₅; NMR (DMSO-d₆) δ: 1.37 (s, 9H); 1.79(m, 1H); 2.07 (m, 1H); 3.08 (m, 1H); 3.24 (m overlapping H₂O, ˜1H); 3.36(m, 1H); 3.48 (tm, 1H); 3.53 (d, 1H); 3.63 (d, 1H); 3.74 (dd, 1H); 3.99(t, 1H); 4.04 (m, 1H); 4.63 (m, 1H); 5.15 (s, 1H); 6.71 (t, 1H); 7.08(dd overlapping br, 2H); 7.39 (dd, 1H).

3-(4-((3S)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example67, starting from3-(4-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-hydroxymethyl)oxazolidin-2-one(3.95 g, 10 mmol), and purifying by flash chromatography on silica,eluting with a gradient increasing in polarity from 0 to 20% EtOAc indichloromethane. Relevant fractions were combined, evaporated, and theresidue recrystallised from toluene (100 ml) to give the desired product(2.34 g).

MS (ESP): 463 (MH⁺) for C₂₂H₂₇FN₄O₆; NMR (DMSO-d₆) δ: 1.37 (s, 9H); 1.81(m, 1H); 2.08 (m, 1H); 3.10 (m, 1H); 3.24 (t, 1H); 3.35 (dd, 1H); 3.47(dd, 1H); 3.83 (dd, 1H); 4.05 (m, 1H); 4.12 (t, 1H); 4.42 (dd, 1H); 4.48(dd, 1H); 5.02 (m, 1H); 6.36 (d, 1H); 6.71 (t, 1H); 7.10 (dd overlappingbr, 2H); 7.38 (dd, 1H); 8.66 (d, 1H).

EXAMPLE 1133-(4-((3S)-3-Acetamido-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3S)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-onehydrochloride salt (170 mg, 0.43 mmol) was stirred in a mixture ofsaturated sodium bicarbonate solution (5 ml) and dichloromethane (5 ml)in an ice-bath. Acetic anhydride (2 mmol) was added dropwise, and themixture stirred 18 hours, allowing the temperature to rise to ambient.Dichloromethane (10 ml) was added, and the mixture filtered throughphase separating paper, the organic layer evaporated, and crystallisedfrom ethanol to give the desired product (108 mg).

MS (ESP): 405 (MH⁺) for C₁₉H₂₁FN₄O₅; NMR (DMSO-d₆) δ: 1.79 (soverlapping m, 4H); 2.11 (hextet, 1H); 3.11 (dt, 1H); 3.24 (t, 1H); 3.42(dd, 1H); 3.50 (m, 1H); 3.84 (dd, 1H); 4.12 (t, 1H); 4.28 (m, 1H); 4.42(dd, 1H); 4.47 (dd, 1H); 5.02 (m, 1H); 6.37 (d, 1H); 6.73 (t, 1H); 7.11(dd, 1H); 7.39 (dd, 1H); 8.08 (d, 1H); 8.67 (d, 1H).

EXAMPLE 1143-(4-((3S)-3-Methylsulfonamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 113, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride salt (170 mg, 0.43 mmol) and methanesulfonyl chloride gavethe desired product (114 mg) after trituration with diethyl ether andisohexane.

MS (ESP): 441 (MH⁺) for C₁₈H₂₁FN₄O₆S; NMR (DMSO-d₆) δ: 1.88 (hextet,1H); 2.18 (hextet, 1H); 2.94 (s, 3H); 3.20 (m, 1H); 3.31 (t, 1H); 3.36(m overlapped by H₂O, ˜1H); 3.56 (m, 1H); 3.84 (dd, 1H); 3.98 (hextet,1H); 4.12 (t, 1H); 4.42 (dd, 1H); 4.47 (dd, 1H); 5.02 (m, 1H); 6.37 (d,1H); 6.74 (t, 1H); 7.12 (dd, 1H); 7.36 (d, 1H); 7.40 (dd, 1H); 8.68 (d,1H).

EXAMPLE 1153-(4-((3S)-3-Methoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 113, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride salt (170 mg, 0.43 mmol) and methyl chloroformate gave thedesired product (114 mg) after trituration with diethyl ether andisohexane.

MS (ESP): 421 (MH⁺) for C₁₉H₂₁FN₄O₆; NMR (DMSO-d₆) δ: 1.82 (hextet, 1H);2.11 (hextet, 1H); 3.14 (m, 1H); 3.27 (m overlapped by H₂O, ˜1H); 3.39(dd, 1H); 3.49 (m, 1H); 3.53 (s, 3H); 3.84 (dd, 1H); 4.11 (t overlappingm, 2H); 4.42 (dd, 1H); 4.45 (dd, 1H); 5.02 (m, 1H); 6.37 (d, 1H); 6.72(t, 1H); 7.11 (dd, 1H); 7.39 (dd, 1H); 7.42 (d, 1H); 8.67 (d, 1H).

EXAMPLE 1163-(4(3S)-3-Acetoxyacetylamino-1-pyrrolidinyl)-3-filuorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 73, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride salt (300 mg, 0.75 mmol) and acetoxyacetyl chloride gavethe desired product (240 mg) after trituration with diethyl ether andisohexane.

MS (ESP): 463 (MH⁺) for C₂₁H₂₃FN₄O₇; NMR (DMSO-d₆) δ: 1.83 (hextet, 1H);2.06 (s, 3H); 2.13 (hextet, 1H); 3.15 (m, 1H); 3.26 (m overlapped byH₂O, ˜1H); 3.41 (dd, 1H); 3.50 (m, 1H); 3.84 (dd, 1H); 4.12 (t, 1H);4.33 (dd, 1H); 4.43 (s, 2H); 4.45 (m, 2H); 5.03 (m, 1H); 6.36 (d, 1H);6.74 (t, 1H); 7.11 (dd, 1H); 7.41 (dd, 1H); 8.24 (d, 1H); 8.66 (d, 1H).

EXAMPLE 1173-(4-((3S)-3-Hydroxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the technique of Example 74, starting from3-(4-((3S)-3-acetoxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one(140 mg, 0.3 mmol) gave the desired product (125 mg) after triturationwith water, diethyl ether and drying.

MS (ESP): 421 (MH⁺) for C₁₉H₂₁FN₄O₆; NMR (DMSO-d₆) δ: 1.91 (hextet, 1H);2.13 (hextet, 1H); 3.18 (m, 1H); 3.29 (m overlapped by H₂O, ˜1H); 3.40(dd, 1H); 3.49 (m, 1H); 3.79 (s, 2H); 3.84 (dd, 1H); 4.13 (t, 1H); 4.37(dd, 1H); 4.46 (m, 2H); 5.02 (m, 1H); 5.36 (s, 1H); 6.36 (d, 1H); 6.74(t, 1H); 7.11 (dd, 1H); 7.40 (dd, 1H); 7.84 (d, 1H); 8.67 (d, 1H).

EXAMPLE 1183-(4-((3S)-3-(2,2-Dimethyl-1,3-dioxolan4(S)-ylcarbonamido)-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3S)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-onehydrochloride salt (270 mg, 0.67 mmol) was stirred in pyridine (5 ml) atambient temperature. A solution of2,2-dimethyl-1,3-dioxolane-4(S)-carbonyl chloride (˜50% strength, 270mg, 0.85 mmol) in dichloromethane (2 ml) was added dropwise, and themixture stirred 18 hours. Solvent was evaporated, and the residuepartitioned between EtOAc (20 ml) and water (20 ml). The organic layerwas washed with 5% aqueous sodium bicarbonate, brine, then dried(magnesium sulfate) and evaporated. The residue was azeotroped withtoluene (15 ml), and purified by chromatography on a 10 g silica MegaBond Elut® column, eluting with a gradient increasing in polarity from 0to 100% EtOAc in dichloromethane. Relevant fractions were combined andevaporated to give the desired product (205 mg).

MS (ESP): 491 (MH⁺) for C₂₃H₂₇FN₄O₇; NMR (DMSO-d₆) δ: 1.32 (s, 1H); 1.37(s, 3H); 1.91 (hextet, 1H); 2.13 (hextet, 1H); 3.23 (m, 1H); 3.29 (moverlapped by H₂O, ˜1H); 3.38 (m, 1H); 3.49 (m, 1H); 3.86 (dd, 1H); 3.94(dd, 1H); 4.14 (t overlapping m, 2H); 4.37 (m, 1H); 4.43 (overlapping m,3H); 5.04 (m, 1H); 6.40 (d, 1H); 6.76 (t, 1H); 7.14 (dd, 1H); 7.42 (dd,1H); 8.00 (d, 1H); 8.69 (d, 1H).

EXAMPLE 1193-(4-((3S)-3-(2(S),3-Dihydroxypropanoylamino)-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-((3S)-3-(2,2-Dimethyl-1,3-dioxolane-4(S)-carbonamido)-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(170 mg, 0.35 mmol) was dissolved in tetrahydrofuran (6 ml), treatedwith 2 M aqueous hydrochloric acid (1 ml), and stirred at ambienttemperature for 17 hours. After dilution with MeOH (10 ml), MP-Carbonatescavenger resin (Argonaut Technologies, 2 g) was added. and the mixturestirred 1 hour. Resin was filtered off, the filtrate evaporated, and theresidue evaporated with MeOH/water (1:1, 10 ml, 3 times). and trituratedwith diethyl ether to give the desired product (125 mg). MS (ESP): 451(MH⁺) for C₂₀H₂₃FN₄O₇.

NMR (DMSO-d₆) δ: 1.91 (hextet, 1H); 2.12 (hextet, 1H); 3.19 (m, 1H);3.28 (m overlapped by H₂O, ˜1H); 3.46 (overlapping m, 3H); 3.56 (m, 1H);3.84 (overlapping m, 2H); 4.13 (t, 1H); 4.33 (dd, 1H); 4.44 (m, 2H);4.68 (t, 1H); 5.02 (m, 1H); 5.49 (d, 1H); 6.39 (d, 1H); 6.76 (t, 1H);7.12 (dd, 1H); 7.43 (dd, 1H); 7.84 (d, 1H); 8.69 (d, 1H).

EXAMPLE 1203-(4-((3S)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

Using essentially the technique of Example 113, starting from3-(4-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one(1 g, 2.09 mmol) gave the title product as its hydrochloride (850 mg).MS (ESP): 380 (MH⁺) for C₁₆H₁₈FN₅O₃S.

NMR (DMSO-d₆) δ: 2.06 (m, 1H); 2.26 (m, 1H); 3.27 (dd, 1H); 3.42 (moverlapped by solvent, 1H); 3.54 (m, 2H); 3.82 (m, 1H); 3.89 (dd, 1H);4.16 (t, 1H); 4.65 (m, 2H); 5.06 (m, 1H); 6.79 (t, 1H); 7.16 (dd, 1H);7.45 (dd, 1H); 8.42 (s, 1H); 8.49 (br, 3H).

The intermediate for this compound was prepared as follows:

3-(4-((3S)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example67, starting from3-(4-((3S)-3-t-butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-hydroxymethyl)oxazolidin-2-one(2.0 g, 5.06 mmol), and purifying by chromatography on a 90 g Biotagesilica column, eluting with a gradient increasing in polarity from 0 to5% EtOAc in dichloromethane. Relevant fractions were combined,evaporated, and the residue recrystallised from toluene (20 ml) to givethe desired product (1.67 g).

MS (ESP): 480 (MH⁺) for C₂₁H₂₆FN₅O₅S; NMR (DMSO-d₆) δ: 1.37 (s, 9H);1.81 (hextet, 1H); 2.08 (hextet, 1H); 3.11 (m, 1H); 3.26 (m overlappedby H₂O, ˜1H); 3.37 (dd, 1H); 3.48 (t, 1H); 3.88 (dd, 1H); 4.05 (m, 1H);4.14 (t, 1H); 4.64 (m, 2H); 5.06 (m, 1H); 6.71 (t, 1H); 7.11 (ddoverlapping br, 2H); 7.48 (dd, 1H); 8.42 (s, 1H).

EXAMPLE 1213-(4-((3S)-3-Acetamido-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example115, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-onehydrochloride salt (250 mg, 0.60 mmol). Work-up involved separating theorganic layer, washing with aqueous sodium dihydrogen phosphate (2%),brine, and drying (magnesium sulfate). Evaporation gave the desiredproduct (170 mg). MS (ESP): 422 (MH⁺) for C₁₈H₂₀FN₅O₄S.

NMR (DMSO-d₆) δ: 1.79 (s overlapping m, 4H); 2.11 (hextet, 1H); 3.11 (m,1H); 3.26 (m overlapped by H₂O, ˜1H); 3.41 (dd, 1H); 3.49 (m, 1H); 3.88(dd, 1H); 4.14 (t, 1H); 4.28 (dd, 1H); 4.65 (m, 2H); 5.07 (m, 1H); 6.74(t, 1H); 7.11 (dd, 1H); 7.42 (dd, 1H); 8.08 (d, 1H); 8.42 (s, 1H).

EXAMPLE 1223-(4-((3S)-3-Methanesulfonamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example115, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-onehydrochloride salt (250 mg, 0.60 mmol) and methanesulfonyl chloride. Thesame work-up gave the desired product (183 mg).

MS (ESP): 458 (MH⁺) for C₁₇H₂₀FN₅O₅S₂; NMR (DMSO-d₆) δ: 1.87 (hextet,1H); 2.20 (hextet, 1H); 2.94 (s, 3H) 3.21 (m, 1H); 3.31 (t, 1H); 3.38 (moverlapped by H₂O, ˜1H); 3.56 (m, 1H); 3.89 (dd, 1H); 3.98 (dd, 1H);4.15 (t, 1H); 4.65 (m, 2H); 5.07 (m, 1H); 6.74 (t, 1H); 7.13 (dd, 1H);7.36 (d, 1H); 7.40 (dd, 1H); 8.42 (s, 1H).

EXAMPLE 1233-(4-((3S)-3-Acetoxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example73, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one hydrochloride salt (350 mg, 0.84 mmol) andacetoxy,acetyl chloride. Work-up involved separating the organic layer,washing with aqueous sodium dihydrogen phosphate (10%), aqueous sodiumbicarbonate (5%), and drying (magnesium sulfate). Evaporation andtrituration with diethyl ether/isohexane (1:1, 10 ml) gave the desiredproduct (187 mg).

MS (ESP): 480 (MH⁺) for C₂₀H₂₂FN₅O₈; NMR (DMSO-d₆) δ: 1.86 (hextet, 1H);2.07 (s, 3H); 2.14 (hextet, 1H); 3.16 (m, 1H); 3.26 (m overlapped byH₂O, ˜1H); 3.42 (m, 1H); 3.51 (dd, 1H); 3.89 (dd, 1H); 4.14 (t, 1H);4.33 (hextet, 1H); 4.43 (s, 2H); 4.67 (m, 2H); 5.07 (m, 1H); 6.76 (t,1H); 7.14 (dd, 1H); 7.43 (dd, 1H); 8.26 (d, 1H); 8.45 (s, 1H).

EXAMPLE 1243-(4-((3S)-3-Hydroxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example74, starting from3-(4-((3S)-3-acetoxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one(136 mg, 0.28 mmol). Evaporation of the reaction mixture and triturationof the residue with water gave the desired product (0.27 g). MS (ESP):438 (MH⁺) for C₁₈H₂₀FN₅O₅S.

NMR (DMSO-d₆) δ: 1.92 (hextet, 1H); 2.16 (hextet, 1H); ˜3.20 (m,overlapped by H₂O, ˜3H); 3.51 (m, overlapped by H₂O, ˜1H); 3.81 (s, 2H);3.91 (dd, 1H); 4.15 (t, 1H); 4.38 (hextet, 1H); 4.67 (m, 2H); 5.08 (m,1H); 6.75 (t, 1H); 7.12 (dd, 1H); 7.41 (dd, 1H); 7.87 (d, 1H); 8.45 (s,1H).

EXAMPLE 1253-(4-((3S)-3-Methoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example115, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-onehydrochloride salt (152 mg, 0.37 mmol) and methyl chloroformate. Work-upand trituration with diethyl ether gave the desired product (53 mg). MS(ESP): 438 (MH⁺) for C₁₈H₂₀FN₅O₅S.

NMR (DMSO-d₆) δ: 1.83 (hextet, 1H); 2.12 (hextet, 1H); 3.16 (m, 1H);3.28 (m overlapped by H₂O, ˜1H); 3.41 (dd, 1H); 3.53 (s overlapping m,4H); 3.89 (dd, 1H); 4.08 (m, 1H); 4.14 (t, 1H); 4.64 (m, 2H); 5.06 (m,1H); 6.74 (t, 1H); 7.12 (dd, 1H); 7.40 (dd, 1H); 7.43 (s, 1H); 8.45 (s,1H).

EXAMPLE 1263-(4-((3S)-3-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonamido)-1-pyrrolidinyl)-3-fuorophenyl)-5(R)-(3-(1,2,5-thiadiazolyloxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example115, starting from3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-onehydrochloride salt (336 mg, 0.81 mmol). Work-up and chromatography gavethe desired product (210 mg).

MS (ESP): 508 (MH⁺) for C₂₂H₂₆FN₅O₆S; NMR (DMSO-d₆) δ: 1.32 (s, 3H);1.38 (s, 3H); 1.89 (hextet, 1H); 2.13 (hextet, 1H); 3.21 (m overlappedby H₂O, ˜2H); 3.38 (t, 1H); 3.48 (m, 1H); 3.90 (dd, 1H); 3.92 (dd, 1H);4.12 (dd, 1H); 4.14 (t, 1H); 4.37 (dd, 1H); 4.42 (t, 1H); 4.64 (m, 2H);5.06 (m, 1H); 6.74 (t, 1H); 7.11 (dd, 1H); 7.40 (dd, 1H); 7.94 (d, 1H);8.42 (d, 1H).

EXAMPLE 1273-(4-((3S)-3-(2(S),3-Dihydroxypropanoylamino)-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

The title compound was prepared using essentially the method of Example119, starting from3-(4-((3S)-3-((4S)-2,2-dimethyl-1,3-dioxoiane-4-carbonamido)-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one(165 mg, 0.33 mmol). For work-up the aqueous organics were treated withsolid potassium carbonate, filtered and evaporated to dryness and theresidue triturated with diethyl ether to give the desired product (90mg).

MS (ESP): 468 (MH⁺) for C₁₉H₂₂FN₅O₆S; NMR (DMSO-d₆) δ: 1.92 (hextet,1H); 2.13 (hextet, 1H); 3.17 (m, 1H); 3.30 (m overlapped by H₂O, ˜1H);3.48 (overlapping m, 3H); 3.56 (m, 1H); 3.87 (m, 1H); 3.90 (dd, 1H);4.14 (t, 1H); 4.34 (hextet, 1H); 4.66 (overlapping m, 3H); 5.07 (m, 1H);5.48 (br, 1H); 6.76 (t, 1H); 7.13 (dd, 1H); 7.43 (dd, 1H); 7.85 (d, 1H),8.46 (s, 1H).

EXAMPLE 1283-(4-(4-(6-Cyano-3-pyridazinyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yl)oxymethyloxazolidin-2-one

3-(4-(4-(6-Cyano-3-pyridazinyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (398 mg, 1 mmol), 3-hydroxyisoxazole (93.5 mg,1.1 mmol) and triphenylphosphine (328 mg, 1.25 mmol), were suspendedwith stirring in dry tetrahydrofiran (10 ml).Diisopropylazodicarboxylate (242 mg, 1.2 mmol) was added dropwise bysyringe, and the mixture stirred at ambient temperature for 30 minutes.The reaction mixture was filtered, evaporated to dryness, dissolved inEtOAc/isohexane (1:1), and applied to a 10 g silica Mega Bond Elut®column, eluting with a gradient from 75 to 100% EtOAc in isohexane.Relevant fractions were combined and evaporated to give the titlecompound (120 mg).

MS (ESP): 466 (MH⁺) for C₂₂H₂₀FN₇O₄; NMR (DMSO-d₆) δ: 3.08 (t, 4H); 3.89(overlapping m, 5H); 4.16 (t, 1H); 4.45 (m, 2H); 5.05 (m, 1H); 6.37 (d,1H); 7.10 (t, 1H); 7.21 (dd, 1H); 7.40 (d, 1H); 7.53 (dd, 1H); 7.88 (d,1H); 8.67 (d, 1H).

The intermediates for this compound were prepared as follows:

3-(3-Fluoro-4-(piperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-onehydrochloride

3-(3-Fluoro-4-(4-t-butoxycarbonylpiperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(WO 93/23384; 43.1 g, 0.11 M) was suspended by stirring in ethanol (1000ml) under nitrogen. An ethanol solution of hydrogen chloride (3.8 M, 400ml) was added slowly, to give a solution. The mixture was stirred atambient temperature for 18 hours. The resulting precipitate wasfiltered, washed with diethyl ether (3×250 ml), and dried, to give thetitle product. A further crop was obtained by evaporation of the motherliquors. Total vield: 38.7 g.

MS (ESP): 296 (MH⁺) for C₁₄H₁₈FN₃O₃; NMR (DMSO-d₆) δ: 3.17 (m, 8H); 3.53(dd, 1H); 3.64 (dd, 1H); 3.79 (dd, 1H); 4.03 (t, 1H); 4.66 (m, 1H); 7.10(t, 1H); 7.21 (dd, 1H); 7.52 (dd, 1H); 9.39 (br s, 2H).

3-(4-(4-(6-cyano-3-pyridazinyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one

3-(3-Fluoro4-(piperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-onehydrochloride (6.63 g, 20 mmol) was suspended by stirring inacetonitrile (200 ml) under nitrogen, and triethylamine (4.44 g, 44mmol) added. The mixture was stirred for 10 minutes3-chloro-6-cyanopyridazine (2.79 g, 20 mmol) added, and the mixtureheated under reflux for 18 hours. After cooling, solid was filtered,washed with water (3×150 ml) and diethyl ether (2×150 ml) to give thetitle product (6.3 g).

MS (ESP): 398 (MH⁺) for C₂₀H₂₀FN5O₃; NMR (DMSO-d₆) δ: 3.03 (t, 4H); 3.54(m, 1H); 3.63 (m, 1H); 3.78 (t overlapping m, 5H); 4.03 (t, 1H); 4.66(m, 1H); 5.18 (t, 1H); 6.97 (d, 1H); 7.07 (t, 1H); 7.20 (dd, 1H); 7.53(dd, 1H); 7.85 (dd, 1H); 8.49 (d, 1H).

EXAMPLE 1293-(3-Fluoro4-(2-methyl-imidazol-1-yl)phenyl)-5(R)-(3-(1,2,5-thiadiazolyl)oxymethyl)oxazolidin-2-one

Using essentially the same procedure as for the intermediate of Example65, but starting with3-(3-fluoro-4-(2-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(582 mg, 2.0 mmol) and 3-hydroxy-1,2,5-thiadiazole (224 mg, 2.2 mmol),and purifying by chromatography on a 10 g silica Mega Bond Elut® column,eluting with a gradient increasing in polarity from 0 to 10% MeOH indichloro-methane, the title compound was prepared (160 mg).

MS (ESP): 376 (MH⁺) for C₁₆H₁₄FN₅O₃S; NMR (DMSO-d₆) δ: 2.15 (s, 3H);4.02 (dd, 1H); 4.27 (t, 1H); 4.66 (dd, 1H); 4.72 (dd, 1H); 5.18 (m, 1H);6.92 (d, 1H); 7.20 (d, 1H); 7.48 (dd, 1H); 7.55 (t, 1H); 7.74 (dd, 1H);8.42 (s, 1H).

EXAMPLE 1303-(4-(4-Hydroxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-(3—(1,2,5-thiadiazolyl)methyl)oxazolidin-2-one

Essentially the same procedure as for the intermediate of Example 65 wasused, but starting with3-(4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)-3-fluoro-phenyl)-5(R)-hydroxymethyloxazolidin-2-one(842 mg, 2.0 mmol) and 3-hydroxy-1,2,5-thiadiazole (224 mg, 2.2 mmol).After filtration of reduced azo compound, the solution was treated with10% TFA in acetonitrile (10 ml), evaporated to dryness and purified bychromatography on a 10 g silica Mega Bond Elut® column, eluting with agradient increasing in polarity from 0 to 20% MeOH in dichloromethane,to give the title compound (65 mg). MS (ESP): 392 (MH⁺) forC₁₆H₁₄FN₅O₄S.

NMR (DMSO-d₆) δ: 4.02 (dd, 1H); 4.27 (t, 1H); 4.50 (s, 2H); 4.60 (br,1H); 4.66 (dd, 1H); 4.72 (dd, 1H); 5.18 (m, 1H); 7.53 (dd, 1H); 7.69 (s,1H); 7.74 (t, 1H); 7.80 (dd, 1H); 8.42 (s, 1H); 8.81 (s, 1H).

EXAMPLE 1313-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylmethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(1,2,5,6-Tetrahydro4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-onehydrochloride (144 mg, 0.36 mmol) was stirred in dichloromethane (5 ml)at ambient temperature, and treated with diisopropylethylamine (67 mg,0.52 mmol) to give a solution. A solution of(4S)-2,2-dimethyl4-(1,3-dioxolane)methyl 4-nitrophenyl carbonate (202mg, 0.68 mmol) in dichloromethane (2.5 ml) was added dropwise, and themixture stirred 18 hours. The mixture was diluted with dichloromethane(10 ml), and washed with water (4×15 ml). After drying (magnesiumsulfate), the residue after evaporation was purified by chromatographyon a 10 g silica Mega Bond Elut® column, eluting with a gradientincreasing in polarity from 0 to 5% MeOH in dichloromethane. Relevantfractions were combined and evaporated to give the desired product (152mg). MS (ESP): 518 (MH⁺) for C₂₅H₂₈FN₃O₈.

NMR (DMSO-d₆) δ: 1.26 (s, 3H); 1.31 (s, 3H); 2.43 (m, 2H); 3.56 (m, 2H);3.69 (dd, 1H); 3.92 (dd, 1H); 4.02 (overlapping m, 4H); 4.11 (dd, 1H);4.20 (t, 1H); 4.25 (m, 1H); 4.44 (dd, 1H); 4.49 (dd, 1H); 5.06 (m, 1H);5.98 (br s, 1H); 6.36 (d, 1H); 7.31 (dd, 1H); 7.37 (t, 1H); 7.49 (dd,1H); 8.66 (d, 1H).

EXAMPLE 1323-(4-(1-(2(S),3-Dihydroxypropyloxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylmethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(130 mg, 0.25 mmol) was dissolved in tetrahydrofuran (5 ml), treatedwith 2 M aqueous hydrochloric acid (2 ml), and stirred at ambienttemperature for 72 hours. Excess potassium carbonate was added to removeacid and water, and the solution filtered. The filtrate was evaporated,and the residue purified by chromatography on a 10 g silica Biotagecolumn, eluting with a gradient increasing in polarity from 0 to 10%MeOH in dichloromethane. Relevant fractions were combined and evaporatedto give the desired product (103 mg). MS (ESP): 478 (MH⁺) forC₂₂H₂₄FN₃O₈.

NMR (DMSO-d6) δ: 2.42 (m, 2H); 3.37 (t, 2H); 3.57 (m, 2H); 3.65 (dd,1H); 3.93 (overlapping m, 2H); 4.06 (overlapping m, 3H); 4.19 (t, 1H);4.47 (m, 2H); 4.59 (t, 1H); 4.84 (d, 1H); 5.07 (m, 1H); 5.99 (br s, 1H);6.37 (d, 1H); 7.32 (dd, 1H); 7.39 (t, 1H); 7.51 (dd, 1H); 8.78 (d, 1H).

EXAMPLE 1333-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylmethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the same procedure as for Example 131, but startingwith3-(4-(1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride (151 mg, 0.36 mmol), gave the title compound (170 mg).

MS (ESP): 536 (MH⁺) for C₂₅H₂₇F₂N₃O₈; NMR (DMSO-d₆) δ: 1.26 (s, 3H);1.32 (s, 3H); 2.31 (m, 2H); 3.58 (m, 2H); 3.69 (dd, 1H); 3.91 (dd, 11H);4.03 (overlapping m, 4H); 4.12 (dd, 1H); 4.18 (t, 1H); 4.26 (m, 1H);4.43 (m, 2H); 5.08 (m, 1H); 5.85 (br s, 1H); 6.37 (d, 1H); 7.34 (d, 2H);8.67 (d, 1H).

EXAMPLE 1343-(4-(1-(2(S),3-Dihydroxypronyloxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using essentially the same procedure as for Example 132, but startingwith3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylmethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(140 mg, 0.26 mmol), gave the title compound (116 mg). MS (ESP): 496(MH⁺) for C₂₂H₂₃F₂N₃O₈.

NMR (DMSO-d₆) δ: 2.32 (m, 2H); 3.36 (t, 2H); 3.59 (m, 2H); 3.66 (dd,1H); 3.94 (overlapping m, 2H); 4.06 (overlapping m, 3H); 4.19 (t, 1H);4.49 (m, 2H); 4.57 (t, 1H); 4.85 (d, 1H); 5.10 (m, 1H); 5.87 (br s, 1H);6.37 (d, 1H); 7.34 (d, 2H); 8.78 (d, 1H).

EXAMPLE 1353-(4-(1-(2-Hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Resin bound3-(4-(1-(2-hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(200 mg, 0.118 mmol) was swelled in dichloromethane (2 ml) over 1 hour.Solvent was drained, and the resin treated with TFA (1% indichloromethane, 2 ml), to develop a red colour from bound tritylcation. The resin was washed with dichloromethane (6×1 ml), and thecombined washings evaporated to dryness, then azeotroped with 3 portionsof isohexane/dichloromethane to give the title compound (46 mg) as awhite powder.

MS (ESP): 448 (MH⁺) for C₂₁H₂₂FN₃O₇. NMR (DMSO-d₆) δ: 2.42 (m, 2H); 3.56(m, 4H); 3.92 dd, 1H); 4.02 (m, 4H); 4.19 (t, 1H); 4.45 (m, 2H); 5.07(m, 1H); 5.98 (s, 1H); 6.36 (d, 1H); 7.32 (dd, 1H); 7.39 (t, 1H); 7.48(dd, 1H); 8.66 (d, 1H).

The intermediate for this compound was prepared as follows:

Resin bound 2-hydroxyethyl 4-nitrophenyl carbonate Ethylene glycol2-chlorotrityl resin (Novabiochem, polystyrene backbone, 0.59 mmol /g,400 mg, 0.236 mmol) was swelled in based washed dichloromethane (2 ml)over 30 minutes. Solvent was drained, and a premixed solution of4-nitrophenyl chloroformate (237 mg, 1.18 mmol) and triethylamine (357mg, 3.54 mmol) in base washed dichloromethane (2 ml) was added, and themixture shaken for 18 hours. Solvent and reagents were drained, and theresin washed with dichloromethane (6×1 ml), then diethyl ether (2×2 ml)to give title product. IR (single bead) v: 1767 cm⁻¹

Resin bound3-(4-(1-(2-hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Resin bound 2-hydroxyethyl 4-nitrophenyl carbonate (200 mg, 0.118 mmol)was swelled in based washed dichloromethane (2 ml) over 30 minutes.Solvent was drained, and a premixed solution of1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyi)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-onehydrochloride (233 mg, 0.59 mmol) and diisopropylethylamine (227 mg,1.77 mmol) in base washed dichloromethane (3 ml) was added, and themixture shaken for 6 hours. Solvent and reagents were drained, and theresin washed with dichloromethane (6×1 ml), then diethyl ether (2×2 ml)to give title product. IR (single bead) v: 1761, 1695 cm⁻¹

EXAMPLE 1363-(4-(1-(2-Hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using the same technique as in Example 135 but starting from resin bound3-(4-(1-(2-hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one(200 mg, 0.118 mmol), gave the title compound (44 mg) as a gum. MS(ESP): 466 (MH⁺) for C₂₁H₂₁F₂N₃O₇.

NMR (DMSO-d₆) δ: 2.30 (m, 2H); 3.54 (m, 4H); 3.90 dd, 1H); 4.03 (m, 4H);4.18 (t, 1H); 4.45 (m, 2H); 5.08 (m, 1H); 5.85 (s, 1H); 6.35 (d, 1H);7.32 (d, 2H); 8.66 (d, 1H).

The intermediate for this compound was prepared as follows:

Resin bound3-(4-(1-(2-hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

Using the same technique as in Example 72 but using from3-(4-(1-(2-hydroxyethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-onehydrochloride (244 mg, 0.118 mmol), gave the title product. IR (singlebead) v: 1764, 1696 cm⁻¹

EXAMPLE 1373-(4-(1-Benzyl-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5-(3-methyl-5(R)-isoxazolyloxymethyl)oxazolidin-2-one

3-(4-(1-Benzyl-1,2,5,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one(1.28 g, 3.2 mmol), 3-methyl-5-hydroxyisoxazole (291 mg, 3.5 mmol), andtributylphosphine (0.97 g, 4.8 mmol) were dissolved by stirring in drytetrahydrofuran (20 ml) under nitrogen. The mixture was cooled in anice-bath, and 1,1′-(azodicarbonyl)dipiperidine (1.21 g, 4.8 mmol) addeddropwise over 10 minutes. The solution was stirred 18 hours. allowingthe temperature to rise to ambient. Reduced azo compound was filteredoff, and the solution evaporated to dryness. The residue was purified bychromatography on a 90 g Biotage silica column, eluting with 1:1 diethylether/dichloromethane. Relevant fractions were combined and evaporatedto give the title product (0.58 g). Starting isoxazole described inBull. Soc. Chim. France, 1970, 2690.

MS (ESP): 482 (MH⁺) for C₂₆H₂₅F₂N₃O₄; NMR (500 MHz, DMSO-d₆) δ: 2.20 (s,3H); 2.43 (br s, 2H); 2.70 (t, 2H); 3.18 (m, 2H); 3.65 (s, 2H); 3.95(dd, 2H); 4.13 (t, 1H); 4.40 (dd, 1H); 4.50 (dd, 1H); 4.97 (m, 1H); 5.15(s, 1H); 5.81 (s, 1H); 7.13 (d, 2H); 7.26 (t, 1H); 7.33 (m, 2H); 7.37(m, 1H).

EXAMPLE 138 3-(3-Fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-(5-(12,3-triazolyl)-thiomethyl)oxazolidin-2-one

3-(3-fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one(see Example 141; 369 mg, 1 mmol) and 5-mercapto-1,2,3-tnrazole sodiumsalt (186 mg, 1.5 mmol), were dissolved in DMF (7 ml), then heated at75° for 1 hour. The mixture was diluted with sodium bicarbonate solution(5%, 25 ml), extracted with EtOAc (50 ml), washed with water (2×15 ml),brine (15 ml), dried (magnesium sulfate) and purified by chromatographyon a 10 g silica Mega Bond Elut® column, eluting with a gradientincreasing in polarity from 0 to 10% MeOH in dichloromethane. to givethe title compound (110 mg).

MS (ESP): 375 (MH⁺) for C₁₆H₁₅FN₆O₂S; NMR (DMSO-d₆) δ: 2.14 (s, 3H);3.31 (m, 2H); 3.91 (dd, 1H); 4.26 (t, 1H); 4.89 (m, 1H); 7.22 (s, 1H);7.42 (dd, 1H); 7.61 (t, 1H); 7.73 (dd, 1H); 7.87 (s, 1H); 8.02 (s, 1H);15.23 (br, 1H).

EXAMPLE 1393-(3-Fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-(5-(1-methyltetrazolyl)thiomethyl)oxazolidin-2-one

Using the same technique as in Example 138 but starting from1-methyl-5-mercapto-tetrazole (174 mg, 1.5 mmol), gave the titlecompound (220 mg).

MS (ESP): 390 (MH⁺) for C₁₆H₁₆FN₇O₂S; NMR (DMSO-d₆) δ: 2.16 (s, 3H);3.73 (d, 2H); 3.96 (s overlapping dd, 4H); 4.28 (t, 1H); 5.04 (m, 1H);7.22 (s, 1H); 7.45 (dd, 1H); 7.64 (t, 1H); 7.72 (dd, 1H); 7.87 (s, 1H).

EXAMPLE 1403-(4-(4-Methylimidazol-1-yl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)methyl)oxazolidin-2-one

Sodium hydride (50% in oil, 72 mg, 1.5 mmol) was stirred in suspensionin DMF (7 ml) under nitrogen at ambient temperature.3-Hydroxy-1,2,5-thiadiazole (153 mg, 1.5 mmol) was added and stirringcontinued for 10 minutes. then3-(3-fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one(369 mg, 1 mmol) was added and the mixture heated at 750 for 2 hours.The mixture was diluted with sodium bicarbonate solution (5%, 25 ml),extracted with EtOAc (50 ml), washed with water (2×15 ml), brine (15ml), dried (magnesium sulfate) and purified by chromatography on a 10 gsilica Mega Bond Elut® column, eluting with a gradient increasing inpolarity from 0 to 10% MeOH in dichloromethane, to give the titlecompound (330 mg). MS (ESP): 376 (MH⁺) for C₁₆H₁₄FN₅O₃S.

NMR (DMSO-d₆) δ: 2.17 (s, 3H); 4.02 (dd, 1H); 4.26 (t, 1H); 4.80 (m,2H); 5.16 (m, 1H); 7.22 (s, 1H); 7.48 (dd, 1H); 7.63 (t, 1H); 7.77 (dd,1H); 7.88 (s, 1H); 8.47 (s, 1H).

EXAMPLE 1413-(4-5-Methylimidazol-1-yl)-3-fluorophenyl)-5(R)-(3-(1,2,5-thiadiazolyl)methyl)oxazolidin-2-one

Sodium hydride (60% in oil, 110 mg, 2.75 mmol) was added to a solution3-hydroxyisoxazole (229 mg, 2.7 mmol) in DMF (15 ml) under nitrogen at0°, and the mixture stirred 15 minutes. A solution of3-(3-fluoro-4-(5-methyl-imidazol-1-yl)phenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one(680 mg, 1.8 mmol) in DMF (7 ml) was added, and the mixture stirred 18hours at ambient temperature. Solvent was evaporated, the residuedissolved in EtOAc (50 ml), washed with water (2×30 ml), brine (15 ml),dried (magnesium sulfate) and purified by chromatography on a 10 gsilica Mega Bond Elut® column, eluting with a gradient increasing inpolarity from 0 to 3% MeOH in dichloromethane, to give the titlecompound (149 mg).

MS (ESP): 359 (MH⁺) for C₁₇H₁₅FN₄O₄; NMR (CDCl₃) δ: 2.12 (s, 3H); 4.03(dd, 1H); 4.21 (t, 1H); 4.53 (dd, 1H); 4.61 (dd, 1H); 5.08 (m, 1H); 6.01(d, 1H); 6.91 (d, 1H); 7.29 (dd, 1H); 7.36 (t, 1H); 7.48 (d, 1H); 7.71(dd, 1H) 8.16 (d, 1H).

The intermediates for Examples 106, 140 & 141 were prepared as follows:

3-Fluoro-4-(4-methyl-imidazol-1-yl)nitrobenzene and3-fluoro-4-(5-methyl-imidazol-1-yl)nitrobenzene

4-Methylimidazole (45.1 g, 0.55 M) and N,N-diisopropylethylamine (161 g,1.25 M) were dissolved in acetonitrile (800 ml), and3,4-difluoronitrobenzene (79.5 g, 0.5 M) added. The mixture was stirredand heated to reflux under nitrogen for 24 hours. Solvent wasevaporated, the residue dissolved in EtOAc (800 ml), washed with water(400 ml), brine (200 ml), and dried (magnesium sulfate). The residue wasdissolved in toluene (250 ml), treated with charcoal, filtered, anddiluted with hot cyclohexane (75 ml) to crystallise3-fluoro-4-(4-methyl-imidazol-1-yl)nitrobenzene (64.7 g).

MS (ESP): 222 (MH⁺) for C₁₀H₈FN₃O₂; NMR (DMSO-d₆) δ: 2.18 (s, 3H); 7.29(s, 1H); 7.92 (t, 1H); 8.07 (s, 1H); 8.18 (dd, 1H); 8.38 (dd, 1H).

The mother liquors were evaporated, and chromatographed on a 90 gBiotage silica column, eluting with a gradient from dichloromethane to1:1 dichloromethane/acetonitrile. Relevant fractions were combined andevaporated to give a 2:1 mixture of the 5-methyl:4-methyl isomers (8 g).This was then subjected to HPLC on Merck Lichro Prep silica eluting withEtOAc/MeOH (95:5) at 400 ml/min to separate3-fluoro-4-(5-methyl-imidazol-1-yl)nitrobenzene (5.2 g).

NMR (DMSO-d₆) δ: 2.09 (s, 3H); 6.87 (d, 1H); 7.81 (d, 1H); 7.87 (t, 1H);8.23 (dd 1H); 8.42 (dd, 1H). MS (ESP): 222 (MH⁺) for C₁₀H₈FN₃O₂.

5-Amino-2-(4-methyl-imidazol-1-yl)fluorobenzene

3-Fluoro4-(4-methyl-imidazol-1-yl)nitrobenzene (64.7 g, 0.293 M) wasdissolved in a mixture of MeOH (200 ml) and tetrahydrofuran (800 ml),cooled to 0° under nitrogen, and treated with ammonium formate (99.3 g,1.46 M) followed by palladium on charcoal (10%. 2.5 g). The mixture wasstirred at ambient temperature for 48 hours, filtered through celite,celite washed with MeOH (200 ml), and filtrate evaporated to dryness.The residue was partitioned between EtOAc (800 ml) and 10% aqueoussodium bicarbonate (250 ml). The organic layer was separated, washedwith brine (250 ml), dried (magnesium sulfate) and evaporated to givetitle compound (50.6 g).

MS (ESP): 192 (MH⁺) for C₁₀H₁₀FN₃; NMR (DMSO-d₆) δ: 2.12 (s, 3H); 5.60(br s, 2H); 6.42 (dd, 1H); 6.47 (dd, 1H); 6.98 (s, 1H); 7.11 (t, 1H)7.60 (s, 1H).

5-Amino-2-(5-methyl-imidazol-1-yl)fluorobenzene

Using essentially the same procedure as for the 4-methyl isomer, butstarting from 3-fluoro-4-(5-methyl-imidazol-1-yl)nitrobenzene (5.2 g,23.5 mmol) gave the title product (3.45 g). MS (ESP): 192 (MH⁺) forC₁₀H₁₀FN₃;

5-Benzyloxycarbonylamino-2-(4-methyl-imidazol-1-yl)fluorobenzene

5-Amino-2-(4-methyl-imidazol-1-yl)fluorobenzene (50.6 g, 0.265 M) wasdissolved in dry dichloromethane (800 ml) under nitrogen, and cooled to−5°. Pyridine (26.1 g, 0.33 M) was added, followed by benzylchloroformate (49.9 g, 0.292 M) over 30 minutes. The mixture was stirredand the temperature allowed to rise to ambient over 16 hours. Aqueoussodium bicarbonate (5%, 350 ml) was added, the organic layer separated,and the aqueous layer re-extracted with dichloromethane (2×200 ml), andcombined organics dried (magnesium sulfate). After filtration andevaporation, the residue was recrystallised from toluene (300 ml) togive title product (80 g).

MS (ESP): 326 (MH⁺) for C₁₈H₁₆FN₃O₂; NMR (DMSO-d₆) δ: 2.15 (s, 3H); 5.16(s, 2H); 7.13 (s, 1H); 7.31 (dd, 1H); 7.41 (m, 51H); 7.48 (t, 1H); 7.57(dd, 1H); 7.78 (s, 1H); 10.15 (br s, 1H).

5-Benzyloxycarbonylamino-2-(5-methyl-imidazol-1-yl)fluorobenzene

Using essentially the same procedure as for the 4-methyl isomer, butstarting from 5-amino-2-(5-methyl-imidazol-1-yl)fluorobenzene (3.45 g,18.1 mmol) gave the title product (3.35 g), after trituration of thecrude with a mixture of diethyl ether/isohexane (1:1). MS (ESP): 326(MH⁺) for C₁₈H₁₆FN₃O₂; NMR (DMSO-d₆) δ: 2.00 (s, 3H); 5.17 (s 2H); 6.78(s, 1H); 7.37 (overlapping m, 7H); 7.61 (dd, 1H); 7.63 (s, 1H); 10.21(br s, 1H).

3-(3-Fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Benzyloxycarbonylamino-2-(4-methyl-imidazol-1-yl)fluorobenzene (54 g,0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and1,3-dimethyl-2,4,5,6-tetrahydro-2(1H)-pyrimidinone (100 ml) undernitrogen, cooled to −70°, and treated with a solution of n-butyllithium(1.6 M in isohexane, 114 ml), over 30 minutes. After stirring for 30minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M)in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring wascontinued for 16 hours allowing the temperature to rise to ambient. Themixturc was treated with aqueous sodium bicarbonate (5%, 500 ml) andEtOAc (800 ml), and undissolved solid was removed and washed well withdiethyl ether to give title product (16.3 g). The aqueous layer wasfurther extracted with EtOAc (2×750 ml), the combined extracts dried(magnesium sulfate) and evaporated, and the residue triturated withdiethyl ether. The resulting solid was recrystallisd from ethanol togive more product (10.9 g). MS (ESP): 292 (MH⁺) for C₁₄H₁₄FN₃O₃.

NMR (DMSO-d₆) δ: 2.13 (s, 3H); 3.56 (dd, 1H); 3.68 (dd, 1H); 3.86 (dd,1H); 4.11 (t, 1H); 4.73 (m, 1H); 5.21 (br, 1H); 7.18 (s, 1H); 7.45 (dd,1H); 7.60 (t, 1H); 7.73 (dd, 1H); 7.83 (s, 1H).

3-(3-Fluoro-4-(5-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one

5-Benzyloxycarbonylamino-2-(5-methyl-imidazol-1-yl)fluorobenzene (3.2 g,9.85 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen,cooled to −70°, and treated with a solution of n-butyllithium (1.6 M inisohexane, 6.81 ml). After stirring for 20 minutes at −70°,(R)-glycidylbutyrate (1.57 g, 10.09 mmol) was added at −70°. Stirringwas continued for 16 hours allowing the temperature to rise to ambient.The mixture was treated MeOH (10 ml), stirred 15 minutes, then pouredinto aqueous sodium bicarbonate (5%, 100 ml) and extracted with EtOAc(3×40 ml). The combined extracts were washed with brine (20 ml), dried(magnesium sulfate) and evaporated. and the residue purified bychromatography on a 20 g silica Mega Bond Elut® column, eluting with agradient increasing in polarity from 5 to 10% MeOH in dichloromethane.Relevant fractions were combined and evaporated, to give the desiredproduct (0.86 g). MS (ESP): 292 (MH⁺) for C₁₄H₁₄FN₃O₃.

NMR (DMSO-d₆) δ: 2.03 (s, 3H); 3.57 (dt, 1H); 3.69 (dt, 1H); 3.87 (dd,1H); 4.14 (t, 1H); 4.74 (m, 1H); 5.22 (t, 1H); 6.81 (s, 1H); 7.50(overlapping m, 2H); 7.66 (s, 1H); 7.75 (t, 1H).

3-(3-fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one

3-(3-Fluoro-4-(4-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(11.8 g, 40.5 mmol) was stirred in a mixture of pyridine (200 ml) andtriethylamine (4.86 g, 48.2 mmol) under nitrogen in an ice-bath.Methanesulfonyl chloride (5.16 g, 45 mmol) was added dropwise, and themixture stirrd for 2 hours, allowing the temperature to rise to ambient.Solvent was evaporated, and the residue stirred vigorously with amixture of aqueous sodium bicarbonate (5%, 200 ml) and isohexane (200ml). The precipitate was filtered, washed with water then isohexane, anddried. The residue was recrystallised from hot acetone (200 ml) bydilution with isohexane (300 ml) to give the title product (11.7 g), mp151-153°. MS (EI): 369 (M⁺) for C₁₅H₁₆FN₃O₅S.

NMR (DMSO-d₆) δ: 2.16 (s, 3H); 3.27 (s, 3H); 3.88 (dd, 1H); 4.24 (t,1H); 4.47 (dd, 1H); 4.54 (dd, 1H); 5.04 (m, 1H); 7.20 (d, 1H); 7.45 (dd,1H); 7.63 (t, 1H); 7.73 (dd, 1H); 7.85 (t, 1H).

3-(3-fluoro-4-(5-methyl-imidazol-1-yl)phenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one

3-(3-Fluoro-4-(5-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one(0.86 g, 2.96 mmol) was stirred in a mixture of pyridine (30 ml) andtriethylaminc (0.36 g, 3.55 mmol) under nitrogen in an ice-bath.Methanesulfonyl chloride (0.37 g, 3.26 mmol) was added dropwise, and themixture stirrd for 18 hours, allowing the temperature to rise toambient. Solvent was evaporated. and the residue dissolved indichloromethane (50 ml), and washed with aqueous sodium bicarbonate (5%,25 ml), water (2×25 ml), brine (20 ml), and dried (magnesium sulfate).The residue after evaporation was triturated with diethyl ether to givethe title product (0.68 g).

MS (ESP): 370 (MH⁺) for C₁₅H₁₆FN₃O₅S;

EXAMPLE 1425(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-[3,6-dihydro-(2H)-pyran4-yl]-3-fluorophenyl)oxazolidin-2-one

Diisopropylazodicarboxylate (0.22 g, 1.1 mmol) was added dropwise atambient temperature to a stirred solution of5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one(WO97/09328; 0.275 g, 0.93 mmol), 3-hydroxy1,2,5-thiadiazole (Weinstocket al. Journal of Organic Chemistry 32, 2823 [1967]; 0.1 12 g, 1.1 mmol)and triphenylphosphine (0.288 g, 1.1 mmol) in dry THF (7 ml). Thesolution was kept for 1.5 hours. Solvent was evaporated and the residuewas purified by flash column chromatography, eluting withEtOAc/isohexane (1:1) to give the title product (0.256 g , 73%) as asolid (mp 146-148 ° C.). MS: 378 (MH⁺); NMR: 2.4 (1H, bs); 3.78 (3H, t);3.96 (1H, m); 4.2 (3H, m); 4.66 (2H, m); 5.1 (1H, m); 6.05 (1H, s);7.27-7.5 (3H, m); 8.41 (1H, s).

EXAMPLE 1435(R)-(3-Methyl-1,2,5-oxadiazol-5-oxide-4-yl)oxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one

Sodium hydride (28 mg of a 60% suspension in mineral oil, 0.69 mmol) wasadded portionwise to a solution of5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one(0.2 g, 0.69 mmol) in dry dimethoxyethane (3 ml) and the mixture wasstirred for 40 minutes. 3-Methyl-4-nitro-1,2,5-oxadiazole-5-oxide[Nikolaeva et al. Izv. Akad. Nauk SSSR, Ser. Khim. 965 (1972)] (0.1 g,0.69 mmol) was added portionwise over 5 minutes and the cloudy solutionstirred for 40 minutes. Water (20 ml) was added and the mixtureextracted three times with EtOAc. The combined extracts were dried byfiltration through phase separation paper (Whatman 1 PS) and evaporated.The residue was purified by flash column chromatography, eluting withEtOAc/isohexane (7:3) to give the title product (0.112 g, 41%) as asolid mp 138-140° C. NMR(CDCl₃): 2.07 (3H, s); 2.5 (2H, bs); 3.91 (3H,t); 4.2 (1H, t); 4.31 (2H, m); 4.62 (2H, m); 5.06 (1H, m); 6.05 (1H, s);7.2-7.42 (3H, m).

EXAMPLE 1445(R)-(2-Methyl-1,3,4-oxadiazol-5-yl)oxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one

Sodium hydride (28 mg of a 60% suspension in mineral oil, 0.69 mmol) wasadded to a solution of5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one(0.2 g, 0.69 mmol) in DMSO (5 ml) and the mixture was stirred for 1hour. 2-Methyl-5-sulfonylmethyl-1,3,4-oxadiazole (RB Woodward et al,(Journal of the American Chemical Society 105, 904 [1983]) (0.11 g, 0.69mmol) was added and the solution heated at 110° C. for 9 hours. Water(40 ml) was added and the mixture extracted three times with EtOAc. Thecombined extracts were dried by filtration through phase separationpaper (Whatman 1PS) and evaporated. The residue was purified by flashcolumn chromatography, eluting first with EtOAc and then with EtOAc/MeOH(20:1) to give the title product (23 mg, 9%) as a solid (mp 146-147°C.). MS: 376 (MH+).

NMR (CDCl₃): 2.41 (3H, s); 2.49 (2H, bs); 3.91 (3H, t); 418 (1H, t);4.31 (2H, m); 4.7 (2H, m); 5.05 (1H, m); 6.04 (1H, s); 7.23 (2H, m); 7.4(1H, d).

EXAMPLE 1455(R)-(5-Methoxycarbonylisoxazol-3-yl)oxymethyl-3-(4-[3,6-dihydro-(2H-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one

Using the method of Example 142 but starting from5-methoxycarbonyl-3-hydroxyisoxazole, the title compound was obtained in65% yield as a solid (mp 145-147° C.). MS: 419 (MH⁺).

NMR (CDCl₃): 2.5 (2H, bs); 3.93 (3H, s+3H, m); 4.18 (1H, t); 4.32 (2H,s); 4.59 (2H, m); 5.04 (1H, m); 6.06 (1H, s); 6.58 (1H, s) 7.24 (2H, m);7.4 (1H, d).

EXAMPLE 1465(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-iodophenyl)oxazolidin-2-one

Iodine (0.67 g, 2.64 mmol) was added portionwise to a stirred solutionof 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2-one (0.7 g,2.53 mmol) and silver trifluoroacetate (0.727 g, 3.29 mmol) inacetonitrile (4 ml) and chloroforrn (6 ml). The mixture was stirred for24 hours in the dark. The mixture was filtered and the filtrateevaporated. The residue was extracted with EtOAc and the extract washedwith water, dilute ammonia (0.1 ml of 0.88SG ammonia in 25 ml water),water and brine, dried (Na₂SO₄) and evaporated to give the title productas a solid (0.749 g, 73%)

MS: 404 (MH⁺); NMR: 3.94 (1H, m); 4.18 (1H, t); 4.67 (2H, m); 5.1 (1H,m); 7.38 (2H, d); 7.7 (2H, d); 8.41 (1H, s).

The necessary starting material,5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2-one, was madeby the method of Example 142, but starting from5(R)-hydroxymethyl-3-phenyloxazolidin-2-one (Gregory, W A. et al, J.Med. Chem. (1989), 32, 1673-81), the title product being obtained as asolid in 83% yield. MS: 278 (MH⁺);

NMR (CDCl₃): 4.0 (1H, m); 4.2 (1H, t); 4.68 (2H, m); 5.04 (1H, m); 7.18(1H, t); 7.4 (2H, t); 7.55 (2H, d); 8.0 (1H, s).

EXAMPLE 1475(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(-4-[2,5-dihydrothiophen-1,1-dioxo-3-yl]phenyl)oxazolidin-2-one

A mixture of5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-iodophenyl)oxazolidin-2-one(Example 146) (0.6 g, 1.49 mmol), 2,5-dihydrothiophen-1,1-dioxide (0.185g, 1.57 mmol), triethylamine (0.26 ml, 01.87 mmol), tetrabutylammoniumbromide (0.48 g, 1.49 mmol) and palladium acetate (17 mg, 0.0759 mmol)in DMF (4 ml) was heated at 60° C. for 19 hours under nitrogen. Aftercooling, the mixture was partitioned between water and EtOAc and theaqueous layer was twice further extracted with EtOAc. The combinedextracts were washed with water and brine, dried (Na₂SO₄) andevaporated. The residue was triturated with acetonitrile to give thetitle product (71 mg, 12%) as a solid. MS: 394 (MH⁺);

NMR (400 MHz): 4.0 (1H, m); 4.1 (21H, m); 4.25 (1H, t); 4.4 (2H, s); 4.7(2H, m); 5.15 (1H, m); 6.57 (1H, s); 7.6 (4H, m); 8.45 (1H, s).

EXAMPLE 1485(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(3-fluoro4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

1N aqueous HCl (1 ml) was added to a solution of5(R)-(1,2,5-thiadiazol-3-yloxymethyl)-3-(3-fluoro4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one(0.154 g, 0.32 mmol) in THF (3 ml) and the solution kept for two days.The solution was evaporated and the residue azeotroped twice withethanol. The residue was purified by chromatography on a BondElut silicacolumn, eluting first with dichloromethane and then 2%MeOH/dichloromethane to give the title product (37 mg, 26%) as a solid.MS: 465 (MH⁺); NMR(400 MHz): 2.5 (2H+DMSO); 3.3 (1H, s)3.4 (1H, m); 3.5(1H, m); 3.76 (1H, m); 4.0 (1H, t); 4.15 (1H, s); 4.26 (1H, t); 4.4 (1H,m); 4.8 (3H, m); 4.97 (1H, m); 5.18 (1H, m); 6.03 (1H, s); 7.32-7.46(2H, m); 7.53 (1H, d); 8.47 (1H, s).

The necessary starting material was made by the method of Example 142,but starting from5(R)-hydroxymethyl-3-(3-fluoro-4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one(prepared by analogy to Example 1H) to give the title product in 56%yield. MS: 505 (MH⁺); NMR; 1.32 (6H, s); 2.41 (2H+DMSO); 3.58 (1H, m);3.66 (2H, m); 3.82 (1H, t); 4.02-4.27 (5H, m); t); 4.69 (1H, m); 4.9(1H, m); 5.19 (1H, t); 6.0 (1H, s); 7.32 (2H, m); 7.5 (1H, d); 8.47.

EXAMPLE 1495(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-(1-(2(R),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl-3-fluorophenyl)oxazolidin-2-one

Using the method described for Example 148, but starting from5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one,the title product was obtained in 50% as a solid. MS: 465 (MH⁺); NMR(400MHz): 2.42 (2H+DMSO); 3.5 (1H, m); 3.58 (1H, m); 3.71 (1H, m); 3.98 (1H,t); 4.1 (1H, s); 4.2 (1H, t); 4.35 (1H, m); 4.77 (3H, m); 4.93 (1H, m);5.12 (1H, m); 6.02 (1H, s); 7.3-7.42 (2H, m); 7.5 (1H, d); 8.42 (1H, s).

The necessary starting material,5(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one, was made as follows:

i)5(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onewas made by the method of Example 142, but starting from5(R)-hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one(WO97/30995 & by analogy to reference Example 4) in 58% yield. MS: 467(MH⁺); NMR; 2.4 (2H+DMSO); 2.6 (2H, m); 3.02 (2H, m); 3.57 (2H, s); 3.92(1H, m); 4.2 (1H, t); 4.62 (2H, m); 5.1 (1H, m); 5.91 (1H, s); 7.2-7.4(7H, m); 7.48 (1H, d); 8.4 (1H, s).

ii) Diisopropylethylamine (0.39 ml, 2.24 mmol) was added dropwise to astirred solution at 5° C. under nitrogen of5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one(3.48 g, 7.47 mmol) in dichloromethane (60 ml), followed by1-chloroethyl chloroforrnate (1.05 ml, 9.73 mmol). The mixture wasstirred at 5° C. for 2 hours and the intermediate carbamate was freedfrom benzyl chloride by flash-column chromatography (silica gel. Merck7736), eluting with a gradient of 10-30% EtOAc in isohexane. Thecarbamate was heated in refluxing MeOH (40 ml) for 1 hour. Solvent wasevaporated and the residue triturated with ether to give5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onehydrochloride as a solid in 82% yield MS: 376 (MH⁺)(free base); NMR;2.67 (2H, s); 3.3 (2H+DMSO); 3.75 (2H, s); 4.0 (1H, m); 4.25 (1H, t);4.7 (2H, m); 5.14 (1H, m); 6.05 (1H, s); 7.4 (2H, m): 7.55 (1H, d); 8.42(1H, s); 9.35 (1H, bs).

iii) A solution of (R)-2,2-dimethyl-1,3-dioxolan-4-ylcarbonyl chloride(S Handa et al, Synth. Commun. (1995), 25, 2837) [0.597 g, 3.63 mmol ]in dichloromethane (5 ml) was added dropwise to a stirred mixture of5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onehydrochloride (1 g, 2.42 mmol) and pyridine (0.49 ml, 6.06 mmol) indichloromethane (30 ml) under nitrogen at −10° C. After 10 minutes thecooling bath was removed and the mixture stirred for a further hour.Water (30 ml) was added and the organic layer washed with brine, dried(Na₂SO₄) and evaporated. The residue was triturated with ether andfiltered to give5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-oneas a solid (1.13 g, 93%) MS: 504 (MH⁺); NMR: 1.32 (6H, s); 2.42(2H+DMSO); 3.7 (2H, m); 4.0 (1H, m); 4.11 (2H, m); 4.25 (2H, m); 4.8(2H, m); 4.91 (1H, m); 5.12 (1H, m); 6.02 (1H, s); 7.29-7.43 (2H, m);7.5 (1H, d); 8.42 (1H, s).

EXAMPLE 1505(R)-1,2,5-Thiadiazol-3-yloxnmethyl-3-(3,5-difluoro-4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

Using the method described for Example 148, but starting from5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3,5-difluoro-4-(1-(2,2-dimethyl-1-3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one,the title compound was obtained in 51% yield as a solid. MS: 483 (MH⁺);NMR: 2.48 (2H+DMSO); 3.48 (1H, m); 3.54 (1H, m); 3.97, (1H, t); 4.1 (1H,s); 4.17 (1H, t); 4.34 (1H, m); 4.67 (3H, m); 4.95 (1H, m); 5.12 (1H,m); 5.88 (1H, s); 7.33 (1H, s); 7.36 (1H, s); 8.42 (1H, s).

The necessary starting material was made as follows:

i) Using the method described for Example 149 step i), but starting from5(R)-hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one, there was obtained in 58% yield,5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3.5-difluorophenyl)oxazolidin-2-one as a solid. MS: 485 (MH⁺); NMR; 2.3 (2H, bs);2.6 (2H, t); 3.03 (2H, s); 3.39 (2H, s); 3.95 (1H, m); 4.2 (1H, t); 4.65(2H, m); 5.12 (1H, s); 5.77 (1H, s); 7.2-7.38 (7H, m); 8.41 (1H, s).

ii) Using the method described for Example 149 step ii), but startingfrom5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one,there was obtained in 84% vield,5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3,5-difluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onehydrochloride as a solid. MS: 395 (MH⁺)(free base); NMR; 2.51 (2H, s);3.28 (2H+DMSO); 3.71 (2H, s); 3.98 (1H, m); 4.2 (1H, t); 4.65 (2H, m);5.1 (1H, m); 5.88 (1H, s); 7.33 (1H, s); 7.39 (1H, s); 8.41 (1H, s);9.32 (1H, bs).

iii) Using the method described for Example 149 step iii), but startingfrom,5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3,5-difluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onehydrochloride and the appropriate (S)-dioxolan there was obtained in 86%yield,5(R)-1,2,5-thiadiazol-3-yloxymnethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-oneas a solid. MS: 523 (MH⁺); NMR: 1.31 (6H, 2s); 2.4 (2H+DMSO); 3.6-3.8(2H, m); 4.08-4.2 (5H, m); 4.9 (1H, m); 5.12 (1H, m); 5.89 (1H, s);7.32-7.37 (2H, 2s); 8.41 (1H, s).

EXAMPLE 1515(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one

A saturated solution of ammonia in MeOH (8 ml) was added to a stirredsolution of5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one(0.275 g, 0.576 mmol) in MeOH (8 ml) and the solution kept for 20 hours.A small amount of insoluble material was filtered off and the filtrateconcentrated. On keeping at 5° C., a solid was obtained which wasfiltered and washed with a little cold MeOH and then cold ether to givethe title compound (0.161 g, 64%) as a solid. MS: 435 (MH⁺); NMR: 2.42(2H+DMSO); 3.52 (1H, m); 3.67 (1H, m); 3.94.(1H, m); 4.0-4.17(4H, m);4.2 (1H, t); 4.5-4.73 (3H, m); 5.12 (1H, m); 6.0 (1H, m); 7.28-7.42 (2H,m); 7.5 (1H, dd); 8.42 (1H, s).

The necessary starting material, was made as follows:

Acetoxyacetyl chloride (0.21 ml, 1.95 mmol) was added to a stirredmixture of5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onehydrochloride (product of step ii, Example 149) [0.412 g, 1 mmol] andsodium bicarbonate (0.42 g, 5 mmol) in acetone/water (15 ml, 2:1) at 5°C. The mixture was allowed to warm up to room temperature after 10minutes and stirred for 18 hours. More acetoxyacetyl chloride (0.3 ml)and sodium bicarbonate (0.42 g,) were added and after a further 6 hours.water was added and the mixture extracted three times with EtOAc. Thecombined extracts were washed successively with water, 1N HCl and brine,dried (Na₂SO₄) and evaporated. The residue was triturated with ether andthe solid filtered to give5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one(0.3 g, 63% yield). MS: 477 (MH⁺); NMR: 2.08 (3H, s); 2.42 (2H+DMSO);3.4 (2H, m); 3.98 (1H, m); 4.08 (2H, bs); 4.21 (1H, t); 4.65 (2H, m);4.8 (2H, m); 5.12 (1H, m); 6.0 (1H, m); 7.31 (2H, m); 7.5 (1H, d); 8.4(1H, s).

EXAMPLE 1525(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-{1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]}-3,5-difluorophenyl)oxazolidin-2-one

Using the method described for Example 151, but starting from5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one,the title compound was obtained in 80% yield as a solid.

MS: 453 (MH⁺); NMR: 2.34 (2H, m); 3.54 (1H, m); 3.71 (1H, m); 4.1 (1H,m); 4.05-4.28 (5H, m); 4.2 (1H, t); 4.54-4.72 (3H, m); 5.15 (1H, m);5.89 (1H, m); 7.39 (2H, d); 8.45 (1H, s).

The necessary starting material was made by the method used to make thestarting material for Example 151, but starting from5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3,5-difluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-onehydrochloride (see Example 150 product (ii)) to give the product in 78%yield. MS: 477 (MH⁺); NMR: 2.08 (3H, s); 2.42 (2H+DMSO); 3.4 (2H, m);3.98 (1H, m); 4.08 (2H, bs); 4.21 (1H, t) 4.65 (2H, m); 4.8 (2H, m);5.12 (1H, m); 6.0 (1H, m); 7.31 (2H, m); 7.5 (1H, d); 8.4 (1H, s).

EXAMPLE 1535(R)-Imidazol-2-ylthiomethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one

1,8-Diazabicyclo[5,4,0]undec-7-ene (0.1 ml, 0.674 mmol) was added to astirred suspension of 5(R)-methanesulfonyloxymethyl3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one(prepared from the 5(R)-hydroxymethyl compound (WO97/09328) by reactionwith methylsulfonyl chloride) (0.25 g, 0.674 mmol) and2-mercaptoimidazole (0.067 g, 0.674 mmol) in dioxan (2 ml) undernitrogen. The mixture was heated at 60° C. for 4 hours and evaporated.The residue was purified by column chromatography, eluting first with 2%MeOH/EtOAc and then with 4% MeOH/EtOAc to give the title product as asolid (0.077 g, 30%); mp 178-179° C. (dec.) MS: 476 (MH⁺); NMR: 2.39(2H, bs); 3.42 (2H, m); 3.79 (2H, t); 3.86 (1H, m); 4.19 (3H, m); 4.89(1H, m); 6.07 (1H, s); 7.04 (2H, s); 7.26 (1H, dd); 7.38 (1H, t); 7.46(1H, d).

EXAMPLE 154 5(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-((1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}hentan-5-yl)-3-fluorophenyl)oxazolidin-2-one

A mixture of1-amino-4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluorobenzene(0.13 g, 0.43 8 mmol) and 3(S)-oxiranylmethoxy-1,2,5-thiadiazole (0.069g, 0.483 mmol) in MeOH (2 ml) was stirred and heated at 60° C. for 20hours. Solvent was evaporated and the residue partially purified byflash column chromatography, eluting with 4/96/0.8MeOH/dichloromethane/0.88SG ammonia. The resulting crude ethanolamine(0.144 g), with diethyl carbonate (0.2 ml), sodium methoxide (9 mg) andMeOH (0.05 ml) was stirred and heated at 110° C. for 5 hours. Thereaction mixture was purified by flash column chromatography, elutingwith EtOAc/0.1% 0.88SG ammonia to give an oil which was triturated withether to give the title product as a solid (mp 97-98° C.) (0.049 g, 23%over two stages). MS: 482 (MH⁺); NMR(CDCl₃); 1.83-2.0 (2H, dd);2.72-2.96 (2H, dd); 3.41 (1H, m); 3.5 (2H, s); 3.91 (1H, m); 4.13 (1H,t); 4.3 (1H, s); 4.67 (2H, m); 5.0 (1H, m); 6.6 (1H, t); 7.05 (1H, dd);7.2-7.38 (6H, m); 8.02 (1H, s).

The necessary starting materials were made as follows:

1-Amino-4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluorobenzene:

i) A mixture of (1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptanedihydrobromide [Henry et al. J. Med. Chem. (1974), 17, 481] (1.05 g, 3mmol), 3,4-difluoronitrobenzene (0.48 g, 3 mmol) and1,8-diazabicyclo[5,4,0]undec-7-ene (1.38 g, 9 mmol) in acetonitrile (10ml) was stirred and heated at reflux for 2 hours. Solvent was evaporatedand the residue was partitioned between EtOAc and water. The organiclayer was filtered (1PS paper) and the filtrate evaporated to give4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluoro-1-nitrobenzene(0.95 g, 97%) as a solid. MS: 328 (M⁺); NMR(CDCl₃); 1.82-2.07 (2H, dd);2.77-2.98 (2H, dd); 3.59 (2H+1H, s); 3.72 (2H, s); 3.91 (1H, m); 4.58(1H, s); 6.6 (1H, t); 7.2-7.34 (5H+CHCl₃);

ii) Hydrazine hydrate (0.57 ml) was added to a suspension of4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluoro-1-nitrobenzene(1.63 g, 5 mmol) in ethanol (35 ml) with stirring, followed by Raneynickel (˜1 g). The mixture was heated at 60° C. for 1.5 hours. Morehydrazine hydrate (0.2 ml) and Raney nickel (˜0.5 g) were added andheating continued for a further 3 hours. The mixture was cooled andstirred with charcoal (0.5 g) for 1 hour and filtered. The filtrate wasevaporated to give1-amino-4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2.2.1}heptan-5-yl]-3-fluorobenzene(1.28 g, 86%) as an oil. MS: 287 (MH⁺); NMR(CDCl₃); 1.8-1.95 (2H, dd);2.73-2.9 (2H, dd); 3.17-3.5 (5H, m); 3.71 (2H, s); 4.12 (1H, s);6.32-6.52 (3H, m); 7.18-7.35 (5H+CHCl₃).

3(S)-oxiranylmethoxy-1,2,5-thiadiazole:

Diisopropylazodicarboxylate (4.2 g, mmol) was added dropwise at ambienttemperature to a stirred solution of(S)-glycidol (1.54 g),3-hydroxy-1,2,5-thiadiazole (2.12 g, 20.8 mmol) and triphenylphosphine(5.45 g, 20.8 mmol) in dry THF (25 ml). The solution was kept for 21hours. Solvent was evaporated and the residue was extracted twice withisohexane (2×50 ml). The combined extracts were evaporated and theresidue purified by flash column chromatography, eluting withEtOAc/isohexane (1:3) to give the title product (0.41 g ) as an oilNMR(CDCl₃); 2.75 (1H, m); 2.9(1H, m); 3.38 (1H, m); 4.28 (1H, m); 4.7(1H, m); 8.0 (1H, s).

EXAMPLE 1555(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-[(1S)(4S)-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluorophenyl)oxazolidin-2-onehydrochloride

Diisopropylethylamine (52 mg, 0.4 mmol) was added dropwise to a stirredsolution at 5° C. under nitrogen of5(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluorophenyl)oxazolidin-2-one(0.65 g, 1.35 mmol) in dichloromethane (10 ml), followed by1-chloroethyl chlorofornate (0.19 ml, 1.76 mmol). The mixture wasstirred at 5° C. for 2 hours and the interrnediate carbamate was freedfrom benzyl chloride by trituration with three portions of isohexane(3×15 ml). The carbarnate was heated in refluxing MeOH (10 ml) for 1hour. Solvent was evaporated and the residue triturated with acetone togive the title product as a solid (0.366 g, 63% yield). MS: 391 (MH⁺);NMR(CDCl₃); 2.0 (2H, dd); 3.2-3.34 (2H+DMSO); 3.56 (2H, dd); 3.9 (1H,m); 4.18 (1H, t); 4.34 (1H, s); 4.5 (1H, s); 5.07 (1H, m); 6.86 (1H, t);7.15 (1H, d); 7.45 (1H, d); 8.42 (1H, s); 9.04 (1H, bs); 9.57 (1H, bs).

EXAMPLE 1565(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-[(1S)(4S)-2-acetoxyacetyl-2,5-diazabicyelo{2,2,1}heptan-5-yl]-3-fluorophenyl)oxazolidin-2-one

Using the method to make the starting material for Example 151 butstarting from the title product of Example 155, the title product wasobtained as an amorphous solid in 46% yield. MS: 491 (MH⁺); NMR(CDCl₃);1.85-2.02 (2H, dd); 2.03 (3H, s); 3.28 (1H, d); 3.57 (1H, s); 3.63-3.83(2H, m); 3.91 (1H, m); 4.1 (1H, t); 4.42-4.73 (5H, m); 5.0 (2H, m); 6.6(1H, m); 7.07 (1H, m); 7.4 (1H, d); 8.01 (1H, s).

EXAMPLE 157 5(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-[(1S)(4S)-2-hydroxyacetyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluorophenyl)oxazolidin-2-one

A solution of the title product of Example 156 (91 mg, 0.185 mmol) inMeOH saturated with ammonia (2.5 ml) was kept for 22 hours. Solvent wasevaporated and the residue was redissolved in dichloromethane (5 ml) andthe solution washed with water. The organic layer was dried byfiltration through phase separation paper (Whatman 1PS) and evaporatedto give the title product as a foam (57 mg, 69%). MS; 450 (MH⁺);NMR(CDCl₃); 1.85-2.17 (2H, m); 3.14-3.84 (5H, m); 3.88-4.29 (4H, m);4.6-4.74 (3H, m); 5.0 (2H, m); 6.6 (1H, m); 7.08 (1H, m); 7.38 (1H d);8.02 (1H, s).

EXAMPLE 1585(R)-1,2,5-Thiadiazol-3-yloxymethyl-3-(4-[(1S)(4S)-2-(2(S),3-dihydroxypropanoyl)-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluorophenyl)oxazolidin-2-one

Using the method to make the starting material for Example 148 butstarting from5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(2-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-2,5-diazabicyclo{2,2,1}heptan-5-yl)phenyl)oxazolidin-2-one,the title product was obtained as an amorphous solid in 79% yield MS:480 (MH⁺); NMR(400 MHz, DMSO-d6+acetic acid-d4); 1.87-2.0 (2H, m); 3.12(1H, m); 3.31 (1H, d); 3.48 (2H, m); 3.65 (2H, m); 3.86 (1H, m); 4.11(1H, m); 4.45 (1H, m); 4.62 (1H, m); 4.78 (1H, m); 5.02 (1H, m); 6.78(1H, m); 7.12 (1H, m); 7.4 (1H, dd); 8.33 (1H, s).

The necessary starting material was made as a solid in 63% yield (MS:520 (MH⁺)) by the method used to make the starting material for Example149 step iii), but starting from the title product of Example 155 andthe appropriate (S)-dioxolan.

EXAMPLE 1595(R)-Isoxazol-3-yloxymethyl-3-(4-{8-acetoxyacetyl-8-azabicyclo[3.2.1]oct-2-ene-3-yl}-3-nluorophenyl)oxazolidin-2-one

Acetoxyacetyl chloride (0.3 ml, 2.72 mmol) was added dropwise to astirred mixture of5(R)-isoxazol-3-yyloxymethyl-3-(4-{8-azabicyclo[3.2.1]oct-2-ene-3-yl}-3-fluorophenyl)oxazolidin-2-one(0.35 g, 0.91 mmol), acetone (7 ml), sodium bicarbonate (0.35 g, 4.17mmol) and water (3.5 ml) and the mixture was stirred for 2 hours. Moresodium bicarbonate (0.7 g) and acetoxyacetyl chloride (0.15 ml) wereadded and after 2.5 hours a further portion of sodium bicarbonate (0.7g) was added and the mixture stirred for 20 hours. Solvent wasevaporated and the residue partitioned between water and EtOAc. Theorganic laver was washed with sodium bicarbonate solution, dried(Na₂SO₄) and evaporated. The residue was purified by chromatography on aMegaBondElut column, eluting with a gradient of dichloromethane-6%MeOH/dichloromethane to give the title product as an oil (0.16 g, 36%).MS: 486 (MH⁺).

NMR(400 MHz): 1.79 (2H, m); 1.88-2.1 (5H, s+m); 2.25 (2H, d); 3.56 (1H,t); 3.62 (1H, m); 3.9 (1H, m); 4.19 (1H, t); 4.48 (3H, m); 4.62 (1H, m);4.78 (2H, m); 5.06 (1H, m); 6.32 (1H, t); 6.35 (1H, s); 7.3 (2H, m);7.48 (1H, dd); 8.66 (1H, s).

The necessary starting material was made as follows:

i) Tris(dibenzylideneacetone) dipalladium(0) (0.19 g, 0.208 mmol),triphenylarsine (0.13 g, 0.425 mmol) and lithium chloride (0.265 g, 6.31mmol) were added to a stirred solution of5(R)-isoxazol-3-yloxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one(prepared by analogy to reference Example 28) (0.85 g, 2.1 mmol) indegassed DMF (35 ml) under nitrogen. After 5 minutes, a solution of8-tert-butyloxycarbonyl-3-trimethylstannyl-8-azabicyclo[3.2.1]oct-2-ene(GB 2298647; 0.78 g, 2.1 mmol) in DMF (4 ml) was added and the mixturewas heated at 60° C. for 18 hours. A solution of 2M potassium fluoride(30 ml) was added and the mixture stirred for 40 minutes. Solvent wasevaporated and the residue partitioned between water and EtOAc. Theaqueous layer was extracted twice with EtOAc and the combined extractsdried (Na₂SO₄) and evaporated. The residue was purified by columnchromatography, eluting with a gradient of dichloromethane-5%MeOH/dichloromethane to give5(R)-isoxazol-3-yloxymethyl-3-(4-{8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene-3-yl}-3-fluorophenyl)oxazolidin-2-one as an oil of 85% purity [hplc](0.97 g,81%). MS: 486 (MH⁺).

ii) Saturated methanolic HCl (1 ml) was added to a solution of theproduct of step i) (0.07 g, 0.144 mmol) in MeOH (1 ml) and the mixturekept for 20 hours. Solvent was evaporated and the residue partitionedbetween water and EtOAc. The organic layer was washed with brine dried(Na₂SO₄) and evaporated to give5(R)-isoxazol-3-yloxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one asan oil (0.03 g, 54% yield). MS: 386 (MH⁺).

EXAMPLE 1605(R)-Isoxazol-3-yloxymethyl-3-(4-{8-hydroxyacetyl-8-azabicyclo[3.2.1]oct-2-ene-3-yl}-3-fluorophenyl)oxazolidin-2-one

Saturated methanolic ammonia (2 ml) was added to a solution of the titleproduct of Example 159 (0.21 g) in MeOH/dichloromethane (1/1, 1 ml) andthe mixture kept for 44 hours. Solvent was evaporated and the residuepurified by chromatography on a MegaBondElut column, euting with agradient of 10% EtOAc/dichloromethane-50% EtOAc/dichloromethane-5%MeOHidichloromethane-10% MeOH/dichloromethane to give the title productas an oil (0.03 g, 27%). MS: 444 (MH⁺); NMR 1.75 (2H, m); 1.98 (2H, m);2.24 (2H, m); 2.82 (1H, bd); 3.9(1H, m); 4.10 (1H, t); 4.19 (1H, t);4.46 (3H, m); 4.66 (14H, t); 5.08 (1H, m); 6.32 (1H, d); 6.36 (1H, s);7.29 (1H, m); 7.34 (1H, m) 7.48 (1H, dd); 8.68 (1H, s).

N.B: The stereochemistry of the azabicyclo rings in Examples 159 and 160is a mixture of (1S),(5R) and (1R),(5S), with the numbering ordered togive the lowest number to the double bond.

EXAMPLE 1613-(4-Methylthio)phenyl-5(R)-(2-thiazoyloxymethyl)oxazolidin-2-one

Sodium hydride (60% w/w in oil, 387 mg, 10 mmol) was washed withisohexane and suspended in DMF (2 ml) under nitrogen.5(R)-hydroxymethyl-3-(4-methylthiophenyl)oxazolidin-2-one (1.39 g, 5.8mmol) was dissolved in DMF and added dropwise to the hydride suspension.Gas was evolved and stirnring at ambient temperature was continued for 2hours, 2-Bromothiazole (0.52 ml, 5.8 mmol) in DMF (10 ml) was addedslowly, an exotherm from 22 to 29° C. was observed. The reaction mixturewas then stirred at ambient temperature for 4 hours and poured intowater. The product was extracted into dichloromethane, dried (MgSO₄) andconcentrated to leave a dark brown gum. The residue was purified byflash chromatography on silica gel, eluting with EtOAc: isohexane, 2:1.The relevant fractions were combined and evaporated to give the productas a white powder (740 mg, mp 83-86° C.).

MS: 322 (M⁺), 323 (MH⁺) for C₁₄H₁₄N₂O₃S₂; NMR (CDCl₃) 7.5 (m, 2H); 7.3(m, 2H); 7.11 (d, 1H); 6.75 (d, 1H); 5.05 (M, 1H); 4.7 (dd, 2H); 4.15(t, 1H); 4.00 (dd, 1H); 2.5 (s, 3H).

EXAMPLE 1623-(4-Methylsulfonylphenyl)-5(R)-(2-thiazoyloxymethyl)-oxazolidin-2-one

3-(4-methylthiophenyl)-5(R)-(2-thiazoyloxymethyl)oxazolidin-2-one (600mg, 2.0 mmol) was dissolved in dichloromethane (20 ml).3-Chloroperoxybenzoic acid (50% w/w, 1.42 g, 4.13 mmol) was addedportionwise maintaining the temperature at <20° C. with externalcooling. A white suspension formed and this was stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated underreduced pressure yielding a white solid. This was triturated twice,initially using diethyl ether and then using dichloromethane leaving theoxidised product as a white powder (285 mg, mp 136° C.). MS: 354 (M⁺),355 (MH⁺) for C₁₄H₁₄N₂O₅S₂.

NMR (DMSO-d₆ ) 7.95 (m, 2H); 7.82 (m, 2H); 7.12 (d, 1H); 6.82 (d, 1H);5.15 (M, 1H); 4.74 (m, 2H); 4.32 (t, 1H); 4.08 (dd, 1H); 3.09 (s, 3H).

EXAMPLE 1633-(4-Methylsulfonylphenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one

5(R)-hydroxymethyl-3-(4-methylthiophenyl)oxazolidin-2-one (see Example42; 1.0 g, 4.18 mmol), 3-hydroxyisoxazole (0.43 g, 5.05 mmol) andtributylphosphine (1.4 g, 5.34 mmol) were suspended in tetrahydrofuran(10 ml) under nitrogen. Diethylazodicarboxylate (0.79 ml, 5.02 mmol) wasadded dropwise. an exotherm from 19 to 33° C. was observed. Theresulting yellow solution was stirred at ambient temperature for 2hours. The complete reaction mixture was then passed down a flashchromatography column using silica gel, eluting with EtOAc: isohexane,7:3. The relevant fractions were combined and evaporated to give impureproduct as a white powder (1.4 g). A portion of this crude material (388mg,) was dissolved in dichloromethane (20 ml). 3-Chloroperoxybenzoicacid (50% w/w, 0.872 g, 2.5 mmol) was added portionwise, maintaining thetemperature at <20° C. with external cooling, the reaction was thenstirred at ambient temperature for 4 hours. The reaction mixture wasconcentrated under reduced pressure yielding a white solid. This wastriturated with diethyl ether and filtered leaving the oxidised productas a white powder (300 mg, mp 180° C.). MS (ESP): 339 (MH⁺) forC₁₄H₁₄N₂O₆S.

NMR (CDCl₃) 8.18 (d, 1H); 7.98 (m, 2H); 7.8 (m, 2H); 6.0 (d, 1H); 5.1(M, 1H); 4.5 (m, 2H); 4.25 (t, 1H); 4.08 (dd, 1H); 3.09 (s, 3H).

EXAMPLE 1645(R)-Isoxazol-3-yloxymethyl-3-(4-bromo-pyrid-2-yl)-oxazolidin-2-one

To a stirred solution of5(R)-hydroxymethyl-3-(4-bromo-pyrid-2-yl)oxazolidin-2-one (EP 694543;3.75 g, 13.7 mmol), 3-hydroxyisoxazole (1.28 g, 15.1 mmol) andtriphenylphosphine(4.31 g, 16.4 mmol) in anhydrous THF (83 ml), wasadded dropwise diisopropyl azodicarboxylate(3.20 g, 3.11 ml, 15.8 mmol)and stirred at room temperature for 5h. The solvent was then removed byrotary evaporation and purification by MPLC (Merck 9385 silica, elutingwith CH₂Cl₂) and trituration with diethyl ether gave the title compoundas a white solid (2.93 g, 63%)

NMR (300 MHz, DMSO-d₆) δ/ppm: 3.98 (dd, 1H), 4.28 (t, 1H), 4.50 (m, 2H),5.08 (m, 1H), 6.38 (d, 1H), 8.07 (br s, 2H), 8.50 (d, 1H), 8.69 (d, 1H).MS: (M+H)⁺=340-Br isotopes.

EXAMPLE 1655(R)-Isoxazol-3-yloxymethyl-3-(4-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)pyrid-2-yl)oxazolidin-2-one

To a stirred solution of Example 164 (340 mg, 1.0 mmol) in anhydrousdeoxygenated DMF (8 ml), under N₂, was added lithium chloride (113.6 mg,3.0 mmol), bis(dibenzylideneacetone)palladium (91.6 mg, 0.10 mmol),triphenylarsine (124 mg, 0.40 mmol) and the vinylstannane(CAS[162046-38-0]; 502 mg, 1.5 mmol) and the reaction mixtureheated to 55° C. and stirred for 64 hours. The solvent was removed byhigh-vac. rotary evaporation giving an oil which was taken into CH₂Cl₂,filtered and purified by MPLC (Merck 9385 silica, eluted with 40%EtOAc/isohexane), to give the title compound as a white powder (202 mg,46%) upon trituration with diethyl ether. MS: (M+H)⁺=443.

NMR (300 MHz, DMSO-d₆) δ/ppm: 1.35 (s, 9H), 2.40 (m, partially obscured,2H), 3.51 (t, 2H), 3.95 (m, 3H), 4.27 (t, 1H), 4.44 (m, 2H), 5.03 (m,1H), 6.13 (br s, 1H), 6.28 (d, 1H), 7.85 (dd, 1H), 8.02 (dd, 1H), 8.38(d, 1H), 8.54 (d, 1H).

REFERENCE EXAMPLE 385(R)-Isoxazol-3-yloxymethyl-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)pyrid-2-yl)oxazolidin-2-one

To Example 165 (185 mg, 0.42 mmol) was added TFA (0.45 ml), withstirring and heating in a water bath at 60° C., for 1 minute, to producean orange/yellow solution which was triturated with diethyl ether togive the title compound as a yellow powder (180 mg, 94%). MS:(M+H)⁺=343.

EXAMPLE 1665(R)-Isoxazol-3-yloxymethyl-3-(4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)pyrid-2-yl)oxazolidin-2-one

Reference Example 38 (58 mg, 0.13 mmol) and triethylamine(71 μl, 0.51mmol) were dissolved in ethyl formate (1.0 ml) and heated to reflux for5 days, followed by removal of the solvent by high-vac rotaryevaporation to give a gum which was redissolved in CH₂Cl₂, washed withwater, concentrated and triturated with diethyl ether to give the titlecompound as a pale yellow powder (38 mg, 81%). MS: (M+H)⁺=371.

NMR (300 MHz, DMSO-d₆) δ/ppm: 2.55 (m, partially obscured, 2H), 3.59 (m,2H), 4.02 (m, 3H), 4.27 (m, 1H), 4.47 (m, 2H), 5.05 (m, 1H), 6.18 (br s,1H), 6.31 (d, 1H), 7.86 (dd, 1H), 8.02 (m, 1H), 8.09 (m, 1H)8.40 (d,1H), 8.61 (d, 1H).

EXAMPLE 1675(R)-(3-Methyl-1,2,4-oxadiazol-5-yloxymethyl)-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one

Prepared by the general method of Example 1 using Reference Example 4(3.57 g, 8.93 mmol), 3-methyl-1,2,4-oxadiazol-5-one (1.00 g, 0.01M),diisopropylazodicarboxylate (2.02 g, 0.01M) and triphenylphosphine (2.81g, 0.011M) in dry THF (70 ml). The resultant product was purified byMPLC (Merck 9385 silica, 20-30% EtOAc in tert-butyl methyl ether plus0.5% MeOH) to give the title compound as a yellow oil (0.340 g, 8%). MS:ESP³⁰ (M+H)⁺=483.

¹H-NMR (300 MHz, CDCl₃): δ=2.27 (s, 3H), 2.44 (m, 2H), 2.60 (t, 2H),3.17 (m, 2H), 3.64 (s, 2H), 3.89 (dd, 1H), 4.12 (m, 1H), 4.62 (m, 2H),5.02 (m, 1H), 5.83 (s, 1H), 7.12 (m, 2H), 7.23-7.41 (m, 5H).

REFERENCE EXAMPLE 395(R)-(3-Methyl-1,2,4-oxadiazol-5-yloxymethyl)-3-(4-(1,2,5,6-tetrahydroyyrid-4-yl)-3,5-dinluorophenyl)oxazolidin-2-one

Prepared by the general method of Reference Example 6, using Example 167(0.33 g, 0.68 mmol), diisopropylamine (0.03 g, 0.21 mmol) and1-chloroethyl chloroformate (0.13 g, 0.89 mmol) in dichloromethane (8ml), to give the title compound as a yellow solid (0.21 g, 72%). MS:ESP⁺ (M+H)⁺=393.

¹H-NMR (300 MHz, DMSO-d₆): δ=2.22 (s, 3H), 2.54 (partially obscured byDMSO, 2H), 3.25 (partially obscured by water, 2H), 3.74 (m, 2H), 3.95,4.20 (dd×2,2H), 4.66 (m, 2H), 5.14 (m, 1H), 5.88 (broad s, 1H), 7.35 (m,2H), 9.25 (broad s, 2H).

EXAMPLE 1685(R)-(3-Methyl-1,2,4-oxadiazol-5-yloxymethyl)-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenylsoxazolidin-2-one

Reference Example 39 (198 mg, 0.46 mmol), and sodium hydrogen carbonate(0.39 g, 4.62 mmol) were stirred in acetone/water (2:1, 9 ml) at 0° C.Acetoxyacetyl chloride (0.13 g, 0.92 mmol) was added dropwise and thereaction mixture was stirred at 0° C. for 30min. Additionalacetoxyacetyl chloride (0.03 g, 0.23 mmol), was added and the mixturewas stirred for a further 30 min. The reaction mixture was diluted withwater and extracted with EtOAc. The combined organic layers were washedwith saturated sodium chloride solution, dried (MgSO₄) and the solventevaporated to give the title compound as a yellow solid aftertrituration with diethyl ether (170 mg, 75%).

¹H-NMR (300 MHz, DMSO-d₆): δ=2.09 (s, 3H), 2.23 (s, 3H), 2.31, 2.43(2×m, 2H), 3.57, 3.66 (2×t, 2H), 3.97, 4.22 (2×dd, 2H), 4.10 (broad d,2H), 4.78 (m, 2H), 4.86 (d, 2H), 5.14 (m, 1H), 5.88 (m, 1H), 7.34 (m,2H), MS: ESP⁺ (M+H)⁺=493.

EXAMPLE 169

The following illustrate representative pharmaceutical dosage formscontaining a compound of the formula (I), an in-vivo hydrolysable esteror a pharmaceutically-acceptable salt thereof, including apharrnaceutically-acceptable salt of an in-vivo hydrolysable ester,(hereafter compound X), for therapeutic or prophylactic use in humans:

Tablet I mg/tablet Compound X 500 Lactose Ph.Eur 430 Croscarmellosesodium 40 Polyvinylpyrrolidone 20 Magnesium stearate 10 Tablet IImg/tablet Compound X 100 Lactose Ph.Eur 179 Croscarmellose sodium 12Polyvinylpyrrolidone 6 Magnesium stearate 3 Tablet III mg/tabletCompound X 50 Lactose Ph.Eur 229 Croscarmellose sodium 12Polyvinylpyrrolidone 6 Magnesium stearate 3 Tablet IV mg/tablet CompoundX 1 Lactose Ph.Eur 92 Croscarmellose sodium 4 Polyvinylpyrrolidone 2Magnesium stearate 1 Capsule mg/capsule Compound X 10 Lactose Ph.Eur 389Croscarmellose sodium 100 Magnesium stearate 1 Injection I Compound X50% w/v Isotonic aqueous solution to 100% Injection II (e.g. bolus)Compound X 10% w/v Isotonic aqueous solution to 100% Injection IIICompound X 5% w/v Isotonic aqueous solution to 100% Injection IV (e.g.infusion) Compound X 1% w/v Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable surfactants, oils or cosolventssuch as polyethylene glycol, polypropylene glycol, glycerol or ethanol,glidants (such as silicon dioxide) or complexing agents such as acyclodextrin (for example, hydroxy-propyl β-cyclodextrin orsulfo-butyl-ether β-cyclodextrin) may be used to aid formulation. Also,improvements in aqueous solubility, if desired, may be achieved. forexample, by conjugation of a compound of formula (I) with a phospholipid(such as a (phospho)choline derivative) to form a micellar emulsion.

Note: The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art, for example as described in“Remington: The Science & Practice of Pharmacy” Vols. I & II (Ed. A.R.Gennaro (Chairman) et al; Publisher: Mack Publishing Company, Easton.Pa.; 19th Edition—1995) and “Pharmaceutics—The Science of Dosage FormDesign” (Ed. M. E. Aulton; Publisher: Churchill Livingstone: firstpublished 1988). The tablets (a)-(d) may be (polymer) coated byconventional means, for example to provide an enteric coating ofcellulose acetate phthalate.

What is claimed is: 1.5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one,or a pharmaceutically-acceptable salt or in vivo-hydrolyzable esterthereof. 2.5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahdropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one, or apharmnaceutically-acceptable salt thereof.
 3. The disodium salt of5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.4. A pharmaceutical composition comprising a pharmaceutically-acceptablediluent or carrier and5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one,or a pharmaceutically-acceptable salt, or in-vivo hydrolysable esterthereof.
 5. A pharmaceutical composition comprising apharmaceutically-acceptable diluent or carrier and5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-oneor a pharmaceutically-acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a pharmaceutically-acceptable diluent or carrierand the disodium salt of5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.7. A method for producing an antibacterial effect in a warm bloodedanimal, comprising administering to the said animal in need thereof aneffective amount of the compound5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-oneor a pharmaceutically-acceptable salt or in vivo-hydrolyzable esterthereof.
 8. A method for producing an antibacterial effect in a warmblooded animal, comprising administering to said animal in need thereofan effective amount of the compound5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one,or a pharmaceutically-acceptable salt thereof.
 9. A method for producingan antibacterial effect in a warm blooded animal, comprisingadministering to said animal in need thereof an effective amount of thedisodium salt of5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.10. A method for producing an antibacterial effect in a warm bloodedanimal, comprising administering to said animal in need thereof aneffective amount of a pharmaceutical composition comprising the compound5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one,or a pharmaceutically-acceptable salt, or in vivo-hydrolyzable esterthereof; and a pharmaceutically-acceptable diluent or carrier.
 11. Amethod for producing an antibacterial effect in a warm blooded animal,comprising administering to said animal in need thereof an effectiveamount of a pharmaceutical composition comprising the compound5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-oneor a pharmaceutically-acceptable salt thereof; and apharmaceutically-acceptable diluent or carrier.
 12. A method forproducing an antibacterial effect in a warm blooded animal, comprisingadministering to said animal in need thereof an effective amount of apharmaceutical composition comprising the disodium salt of5(R)-isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;and a pharmaceutically-acceptable diluent or carrier.